NIDDK Strategic Plan 2000
DRAFT 01/10/00
Message from the Director, NIDDK
As the new Director of the National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK), I am pleased to present to you our
Institute's first five-year Strategic Plan. The strategies outlined
in this plan speak to the opportunities and challenges facing our
Institute, and are the product of the NIDDK's senior scientific
management team, working in collaboration with the National Advisory
Council, the scientific community at large, lay and professional
organizations, and the public.
All agree that much is at stake. The many diseases within the NIDDK's
research mission affect millions of individuals of all ages, are
often chronic in nature, may cause significant morbidity, reduce
life expectancy, and exert an enormous economic burden on society--in
excess of $300 billion annually.
It is our expectation that the successful implementation of our
Strategic Plan will enable the NIDDK to harness the tools, technologies,
and talent needed to further understand, treat, and prevent the
diseases and disorders within our mission while, at the same time,
help us to keep our ultimate goal in sight. That goal is to improve
the quality of life for those afflicted with these diseases, their
families, and society, in general.
Opportunities We See
These are exciting times. Opportunities have never been greater
for scientific discovery made through basic research--and the ability
to adapt and apply those discoveries to clinical settings. The overriding
objective of our Strategic Plan, therefore, is to take full advantage
of the opportunities at hand for the benefit of human health.
The NIDDK's Strategic Plan acknowledges and incorporates into its
objectives the revolution in biomedical research that is being spurred
by a wave of new and improved technologies:
- Gene discovery and genetics research are opening the way to
impressive new approaches in the diagnosis, treatment and prevention
of disease.
- Breakthroughs in basic cell biology are helping to unravel the
complexity of living systems by identifying the impact that subtle
molecular changes have on cells and tissues.
- Advances made through epidemiology and clinical investigation
are making it possible to identify risk factors for the occurrence
and progression of disease, which in turn is stimulating new research
directions and therapeutic approaches.
Challenges We Face
At the same time that our Strategic Plan identifies opportunities,
it also addresses the challenges that need to be overcome in order
to achieve those objectives. Foremost among these challenges, and
a theme that runs throughout the plan, is the need for improved
research infrastructure and capacity, including the need to attract
and retain talented researchers, recruit more volunteers to participate
in the evaluation of new disease treatments, increase the number
of model systems for our studies, and make data more accessible
to a wider range of investigators through the use of new medical
imaging and bioinformatics technologies.
Also, to enhance the mobilization and leveraging of resources to
fight disease, the NIDDK is taking a leadership role in trans-NIH
initiatives, and we believe that the cross-cutting scientific themes
in our Strategic Plan will help to spur this effort as well. In
October 1999, 26 speakers representing voluntary and professional
health organizations concerned about diseases within the NIDDK's
research mission endorsed and commended NIDDK for the cross-cutting
scientific approach and conceptual framework of our plan.
The Course We Are Charting
In addition to our Strategic Plan, this document also includes
an overview of the magnitude of the challenges posed by the diseases
within the NIDDK's mission, a summary of many of the ongoing programs
and mechanisms supported by the NIDDK, examples of the relevance
of cross-cutting scientific research to disease, and an overview
of the process that resulted in our Strategic Plan.
It is our hope that, as you read through this document, you will
gain a deeper understanding of the NIDDK's structure and mission,
as well as the course our Strategic Plan is helping us to chart
so that we can capitalize fully and productively on this era of
unprecedented scientific discovery.
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About the NIDDK
The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) is the fifth largest among the institutes that the National
Institutes of Health (NIH) comprise. The NIDDK conducts and supports
a broad range of fundamental and clinical sciences related to programs
in numerous diseases affecting the public health, including diabetes,
endocrinology, and metabolic diseases; kidney, urologic and blood
diseases; and digestive diseases and nutrition. The economic burden
to society of these diseases is estimated to exceed $300 billion
annually.
The NIDDK also maintains a strong commitment to research training
and research career development, with a special emphasis on the
physician-scientist, as well as our recruiting and retaining under-represented
minorities and women in biomedical research careers.
Because of its broad mission, the NIDDK interacts with more than
100 voluntary health and professional organizations with a special
interest in the Institute's programs.
Divisions That NIDDK Comprises
The NIDDK is composed of four scientific operating divisions and
one administrative division.
The Division of Diabetes, Endocrinology, and Metabolic Diseases
is responsible for extramural research and research training related
to diabetes mellitus; endocrinology, including hormone and growth
factors important in osteoporosis and breast and prostate disease;
and metabolic diseases, including cystic fibrosis.
The Division of Digestive Diseases and Nutrition is responsible
for managing research programs and research training related to
liver and biliary diseases; pancreatic diseases; gastrointestinal
diseases, including motility, immunology, and digestion in the gastrointestinal
tract; nutrient metabolism; obesity; eating disorders; and energy
regulation.
The Division of Kidney, Urologic, and Hematologic Diseases
supports research and research training related to the physiology,
pathophysiology, and diseases of the kidney, genitourinary tract,
and the blood-forming organs to improve or develop preventive, diagnostic,
and treatment methods.
The Division of Intramural Research conducts research and
training within the Institute's laboratories and clinical facilities
in Bethesda, Maryland, and Phoenix, Arizona. The hallmarks of the
NIDDK Intramural program are excellence in scientific productivity
and diversity. The research conducted by this division spans the
breadth of biomedical investigation, from basic science to clinical
studies.
In addition, NIDDK scientific divisions support a variety of trans-NIDDK
and trans-NIH career development and training awards.
The Division of Extramural Activities, an administrative
division, is responsible for issues related to grant and
contract administration and review.
Cross-Cutting Programs
The NIDDK is a strong supporter of research that spans the division
lines, such as studies of diabetes and obesity. The NIDDK's scientific
operating divisions and programs are linked by a shared interest
in the biochemical and genetic processes underlying disease. Close
communication among the NIDDK, other NIH institutes, voluntary and
professional organizations with an interest in the diseases within
the NIDDK's research mission, and related Federal agencies help
to mobilize and leverage the resources in these vital areas of scientific
investigation.
Budget Allocations
The majority of the NIDDK's budget supports investigator-initiated
research grants. During FY 1999, for example, the NIDDK funded 2,653
research grants; 65 research centers; 249 career and other research
awards; 926 research training slots; 68 research and development
contracts; and 20 intramural laboratories and branches. This type
of research investment enables the Institute to maintain a high
degree of budget flexibility so as to take full advantage of newly
emerging scientific opportunities and apply them to the various
needs of its programs and divisions.
To ensure high scientific standards among NIDDK-funded projects,
all grant applications, whether initiated by a researcher or solicited
by the NIH, are evaluated through a two-step peer review process,
mandated by law. That is, all applications are first assessed for
their scientific and technical merit by a group of non-Federal expert
scientists. Applications are then reviewed for program relevance
by the NIDDK National Advisory Council, comprising a group of eminent
scientists and lay individuals.
In FY 1999, the NIDDK invested 70% of its $994 million budget in
investigator-initiated research. About 8% of the NIDDK's FY 1999
grant budget was allocated for clinical trials that support testing
of various methods of therapy and/or prevention in disease areas;
approximately 4% went for Merit Awards to support the work of distinctly
superior researchers identified by the NIDDK National Advisory Council;
and about 8% was in program project grants for the support of broadly
based, multidisciplinary research programs that have specific major
objectives.
As mandated by law, 2.65% of the NIDDK's grant budget was in the
Small Business Innovation Research Program, a mechanism that allows
the government to enter into partnerships with small companies.
In addition to supporting research grants proposed by investigators,
the NIDDK issues research solicitations in the form of Program Announcements
(PAs), Requests for Applications (RFAs) and Requests for Proposals
(RFPs) to stimulate scientific investigations in specific areas.
These solicitations are typically issued to capitalize on compelling
new research findings, and to stimulate research activities in vital
areas of programmatic importance. The NIDDK also leads the development
of, or participates actively in, trans-NIH research solicitations.
The NIDDK sponsors a wide range of scientific conferences and workshops,
ad hoc program planning meetings, and other efforts to secure
external scientific advice and public input into the development
of its grant research portfolio, as well as to recruit new research
talent into specific fields of study. The Institute also encourages
both new and experienced investigators in related disciplines to
expand their efforts to other disciplines.
The 30% of the NIDDK's FY 1999 budget that is not directed to investigator-initiated
research grants was allocated as follows: 5.5% for research centers;
3.3% for research careers and other research; 3.7% for research
training; 3% for research and development contracts; 10.6% for intramural
research; and 2.6% for research management and support, i.e. administrative
costs.
Programs to Enhance the Health of Minorities and Women
The NIDDK participates in a number of programs targeted to under-represented
minorities in biomedical research. Included among these programs
is the NIH Minority Supplement Program that supports minority group
members from secondary schools through to new investigator status.
Another program provides additional positions on training programs
for minorities, principally at the postdoctoral level.
The Institute also awards "re-entry" supplements to research
grants to support women who have completed their research training
but have had to leave research for a period of time, generally because
of family obligations.
With respect to minority health issues, the NIDDK and the Office
of Research on Minority Health have developed an effective and synergistic
partnership over the last few years. By working together, we have
established several major collaborations that assist minority researchers
and benefit research on diseases and disorders within our mission
that disproportionately affect minority populations. We also are
working on concepts to enhance clinical research in minority populations
and at minority research institutions.
In addition, the research programs of the NIDDK are dedicated to
studying chronic diseases of direct relevance to women's health
and also has a strong and synergistic partnership with the Office
of Research on Women's Health. The NIDDK is committed to closing
the gaps in understanding disease processes that pose a special
problem for women and to developing effective preventive and therapeutic
measures in these disease areas.
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Magnitude of the Challenges Facing
the NIDDK
The diseases within the National Institute of Diabetes and Digestive
and Kidney Diseases (NIDDK's) research mission cut across the entire
range of internal medicine and related areas of medical practice,
and are models of the complex interaction of genetic, autoimmune,
neuroendocrine, metabolic, and other mechanisms of disease. Collectively,
these diseases affect virtually every part of the body, from the
level of the cell, to organ systems, to the interactions of the
human body as a whole. They all seriously diminish the quality of
life of those afflicted, their families, and loved ones. In addition,
the health care costs of the diseases represented in NIDDK-supported
research are significantly large segments of the total national
burden of disease, estimated at $1 trillion a year by HCFA.
Documented statistics show, for example, that more than half of
the entire U.S. population is affected by one or more of the diseases
within the NIDDK's research mission, and, according to the Health
Care Financing Administration (HCFA), these diseases consume up
to 30% of the nation's health care costs paid by Medicare.
These numbers are staggering in terms of human life diminished
or lost and dollars spent. However, even these numbers may not reflect
the true impact of these diseases. For example, the death of a diabetic
patient with cardiovascular disease is traditionally recorded as
a cardiovascular death, even though diabetes may have been the root
cause of the individual's cardiovascular condition and resultant
death.
The magnitude of the challenges facing the NIDDK is demonstrated
by the following disease areas for which there are documented statistics.
Keep in mind that the information below does not take into account
the hundreds of conditions related to these major disease areas
for which no reliable data are available.
Endocrine and Metabolic Diseases
Most common among these types of diseases are diabetes and obesity.
Both type 2 diabetes and obesity, for example, involve resistance
to insulin action, which results in an increase in blood lipids
(especially low density lipoprotein and triglycerides) leading to
atherosclerosis, as well as certain defects in cellular signaling.
Kidney disease of diabetes (KDDM), a chronic and disabling complication
of diabetes, is the most common cause of end-stage renal disease
and a perfect example of how certain diseases span the mission of
the NIDDK. Osteoporosis (a condition that results in loss of bone
density) is a severe problem for post-menopausal women while benign
prostatic hypertrophy, more commonly referred to as enlargement
of the prostate, affects a high percentage of men older than 60.
Diabetes
- Affects 16 million people in the U.S.
- 800,000 new cases each year.
- Leading cause of new blindness, end-stage renal disease, and
non-traumatic leg amputations.
- Major risk factor for heart disease, stroke, and birth defects.
- Leading cause of death in people with diabetes is coronary heart
disease.
- Leads to higher death rates from pneumonia, influenza, and many
other illnesses.
- Affects all segments of the population, but manifests highest
incidence in non-Hispanic African Americans, Mexican Americans,
other Latin Americans, Native Americans and Alaskan Natives, as
well as in Asian Americans and Pacific Islanders.
- Cost to nation: More than $98 billion annually, including direct
and indirect costs (i.e. disability, work loss, and premature
death).
- Shortens average life expectancy by up to 15 years.
Obesity
- Affects 60 million people in the U.S. (25% of all women; 20%
of all men; 37% of all minority women).
- Associated with greatly increased risk of complications similar
to those in type 2 diabetes, including cardiovascular problems,
higher levels of harmful lipids in the blood, and increased mortality,
as well as other complications more specific to obesity such as
hypertension; certain cancers; arthritis in the hips, lower back
and legs; gout; and gallbladder disease.
- Increasing in prevalence among children.
- Cost to nation: More than $99 billion annually in both direct
and indirect costs.
Kidney Disease of Diabetes (KDDM)
- Most common cause of end-stage renal disease (ESRD).
- Each year, more than 50,000 people are diagnosed with ESRD caused
by KDDM.
- ESRD, like diabetes and obesity, is most prevalent in African
Americans and Native Americans.
- High blood pressure, as well as high blood sugar levels increase
the risk that a person with diabetes will progress to ESRD.
- Each year, nearly 200,000 Americans undergo dialysis while more
than 12,000 receive kidney transplants.
- Cost to the nation: More than $15.64 billion annually, more
than $10 billion of which comes in the form of Medicare expenditures.
Osteoporosis
- Severe problem for post-menopausal women and older men.
- Responsible for more than 15 million fractures annually, including
hip, vertebrae, and wrist fractures.
- These fractures are a major cause of disability, hospitalization,
and loss of independence, especially for people over the age of
50.
- Cost to the nation: Direct costs of medical care alone are about
$13 billion annually.
Benign Prostatic Hypertrophy (BPH)
- More than half of all men in their sixties, and as many as 90%
in their seventies and eighties, have symptoms of BPH, commonly
known as enlargement of the prostate gland.
- Can lead to incontinence, infections, stones, and kidney damage.
- BPH results in about 375,000 hospital stays each year.
- Although there is no evidence that BPH itself increases the
chances of getting prostate cancer, approximately 30,000 of the
120,000 men each year diagnosed with prostate cancer die of the
disease.
Autoimmune Diseases
An important class of illness is autoimmune diseases, in which
antibodies develop against one's own tissues and harm the affected
organ system. There are many autoimmune diseases for which the NIDDK
has research responsibility. These include: type 1 diabetes; autoimmune
thyroiditis; hyperthyroidism; other autoimmune endocrine syndromes
(including primary adrenocortical insufficiency); autoimmune hepatitis;
primary biliary cirrhosis; primary sclerosing cholangitis; chronic
gastritis; inflammatory bowel disease; glomerulonephritis; lupus
nephritis; and aplastic and hemolytic anemias.
What follows are documented statistics on two of the more prevalent
autoimmune diseases within the NIDDK research mission:
Type 1 Diabetes
- Involves a genetic predisposition and usually begins in childhood.
- Gradually destroys the pancreatic insulin-secreting cells (beta
cells), which leads to life-long dependence on insulin to survive.
- Affects approximately 750,000 to one million Americans, or 5%
to 10% of the 10.3 million people with diagnosed diabetes.
- Complications as a result of type 1 diabetes are essentially
the same as described earlier.
Inflammatory Bowel Disease
- Affects approximately 500,000 Americans each year.
- Results in more than 100,000 doctor visits annually, most of
which (two-thirds) are related to Crohn's Disease, a disorder
affecting primarily the small intestines.
Genetic Diseases
Diabetes and obesity, discussed above, are now being studied for
causative genes along with a host of other disorders, including
several hundred disorders resulting from inborn errors of metabolism.
Now that genes are being identified in many conditions not traditionally
thought of as genetic, the phrase "genetic diseases" has
evolved into a much broader definition than just "inherited
diseases" present from birth. We know, for example, genetic
mutations can cause diseases often precipitated by environmental
triggers. While exacting a heavy toll on those affected, the overwhelming
majority of these genetic disorders are not common enough to have
extensive statistics on their burden of illness. Cystic fibrosis
and polycystic kidney disease (PKD), however, are exceptions.
Cystic Fibrosis (CF)
- One of the most prevalent and tragic genetic diseases of the
young. Approximately 1,000 new cases are diagnosed each year,
usually before 3 years of age.
- Characterized by changes in the functioning of many exocrine
organs as well as excessive production of thick, sticky mucus
in the airways.
- Major gene associated with CF was found in 1989, with subsequent
discovery of protein it produces.
- An individual must inherit two copies of the defective gene--one
from each parent--to acquire the disease. An estimated 8 million
people carry a single copy of the defective gene.
- With improved treatment, CF no longer means death in early childhood;
as a chronic disease, it allows patients to live into their 30s
or 40s.
- Most adult CF patients eventually succumb to lung infections
and respiratory failure.
Polycystic Kidney Disease (PKD)
- Genetic-based disease that results in the development of numerous
cysts in the kidney, liver, and other organs.
- Cysts slowly replace much of the kidney, thereby reducing kidney
function, often leading to kidney failure.
- Causes infections, hematuria, stones, high blood pressure, and
other problems.
- Affects 500,000 Americans and is the fourth leading cause of
kidney failure.
Chronic Infections and Inflammatory Diseases
Viral and bacterial infections not treated or eliminated in the
acute stage go on to produce chronic diseases, such as hepatitis,
nephritis, gastritis (and non-ulcer dyspepsia), pancreatitis, and
others. The impact of such conditions on health and human suffering
is sizeable.
Hepatitis C (HCV)
- The most common blood-borne infection in the U.S. and a major
cause of end-stage liver disease.
- An estimated 4 million Americans are infected with HCV, although
most do not know they carry the virus.
- 85% of those infected become chronic carriers; about 20% develop
cirrhosis, some of whom develop liver cancer.
- Leading cause of liver transplants.
- Causes 8,000 to 10,000 deaths annually. The number is expected
to triple in the next 10 to 20 years.
- Cost to the nation: Approximately $6 billion annually.
Liver Disease
- Chronic liver disease and cirrhosis affect about 400,000 people
annually.
- Each year, chronic liver failure results in an estimated 1 million
doctor visits, 300,000 hospitalizations, more than 100,000 newly
disabled people, approximately 3,300 liver transplants and 26,000
deaths.
Food-borne Illnesses and Chronic Infectious Diarrheas
- Nearly 100 million new cases diagnosed each year resulting in
several thousand deaths annually.
- Hemolytic uremic syndrome is a particularly serious form of
chronic infection in which a bacterial invader (Eschericia
coli O157:H7) may cause destruction of red blood cells, resulting
in kidney damage.
Peptic Ulcers
- Approximately 5 million new cases diagnosed annually.
- Lead to 3 to 5 million doctor visits and nearly 650,000 hospitalizations
each year.
- Bacterial infections (by Helicobacter pylori) appear
to cause at least 2.5 million cases annually.
Common Disorders with Multiple Causes
Kidney Stones in Adults
- Most common disorder of the urinary tract. It is estimated that
10% of all people in the U.S. (men more than women) will form
a kidney stone at some point in their lives.
- Occurrences have increased over the last two decades.
- Commonly caused by excess calcium excreted in the urine, but
also are due to kidney infections, as well as to inherited metabolic
abnormalities.
- Result in an estimated 900,000 doctor visits and more than 300,000
hospitalizations annually.
- Cost to the nation: Approximately $1.9 billion annually.
Gallstones
- Affect 1 in 10 Americans (women more than men) and are associated
with about 3,000 deaths each year.
- Stones large enough to cause pain require 600,000 hospitalizations
and more than 500,000 operations annually.
- Obesity is a strong risk factor for gallstone formation.
- Diets associated with rapid loss of excessive weight also increase
the risk of gallstones.
Gastroesophageal Reflux Disease (GERD)
- Affects more than 60 million American adults at least once a
month; about 25 million adults suffer daily, as do 25% of pregnant
women.
- Major symptoms include heartburn and acid indigestion.
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About the NIDDK Planning Process
The National Institute of Diabetes and Digestive and Kidney Diseases'
(NIDDK's) Strategic Plan, as part of the NIH response to recommendations
of the Institute of Medicine Study on NIH priority-setting and public
input, represents an effort on the part of the NIDDK to identify
and address the global challenges and opportunities it faces in
the next five years with respect to its research mission. The overall
objective of the Plan is to create an environment and strategy within
the NIDDK to support and enhance scientific and clinical research
leading to scientific advances. The ultimate objective, of course,
is to improve the quality of life for those affected by disease,
their families, and society, in general.
The strategies outlined in this plan are not the product of the
Institute acting on its own. Rather, they reflect input to the NIDDK,
working in close collaboration with its National Advisory Council,
the scientific community at large, and lay and professional organizations
with an interest in the disease areas for which the Institute has
research responsibilities.
By design, the NIDDK's Strategic Plan is not a budget or
advocacy document. Nor is it disease specific. Instead, the Plan's
scientific orientation targets the most promising research the Institute
believes is achievable within a five-year time frame, and focuses
on long-term, trans-NIDDK and trans-NIH, cross-cutting scientific
themes. These themes include: genes and their impact on disease;
cell biology; prevention and treatment of disease; and research
infrastructure.
The strategies built around the goals and objectives identified
through these cross-cutting scientific themes are broadly relevant
to a wide range of diseases within the NIDDK research mission.
Scientific Working Groups
The NIDDK's Strategic Plan was developed through a series of scientific
working groups, one group for each of the Strategic Plan's four
themes (see above). Each working group consisted of 12 or more participants,
an NIDDK writing chair, at least one intramural scientist, one lay
person, and at least one member from our National Advisory Council.
The NIDDK Senior Management served as the writing chairs and helped
to cross-fertilize ideas among the working groups.
Working groups were responsible for identifying and emphasizing
the common themes, scientific opportunities, and research challenges
across the programs and divisions of the NIDDK.
Some key features of the planning process that working groups needed
to take into consideration included procuring public involvement
and input, and making the Plan understandable to lay audiences so
as to foster wide distribution.
A Strategy Built Upon the NIDDK's Annual Program Plan
The cross-cutting themes of the NIDDK's Strategic Plan are designed
to help the Institute set a scientific vision to aid in its development
of specific initiatives on an annual basis. As such, the Strategic
Plan complements and builds upon already existing planning processes
within the NIDDK's operating divisions and the Institute as a whole.
Insight into the NIDDK's annual program planning process, therefore,
will provide a greater understanding of the Institute's five-year
Strategic Plan.
The NIDDK Program Plan
Taking into consideration available resources, the NIDDK's annual
program planning process helps guide the development and implementation
of specific research initiatives for each upcoming fiscal year.
It sets a framework for future program activities, as well as for
facilitating the efforts of the NIDDK's scientific and lay constituents.
Each year, this process culminates in the presentation to, and discussion
by, the NIDDK Advisory Council of a planning document called the
"NIDDK Program Plan."
The NIDDK Program Plan contains two major components, which are
presented to the Advisory Council at different times of the year.
The first component is the Research Progress Reviews. These reviews
provide examples of recent major areas of scientific accomplishments
within the NIDDK research mission and are presented to Council in
February.
The second part of the NIDDK Program Plan is the Program
Initiative Concepts component, which is basically a "wish list"
put forth by the NIDDK's three extramural scientific operating divisions.
This component of the Program Plan contains scientific initiative
concepts the divisions would like to see implemented if funding
is made available. Each concept is based on recommendations of the
research community, and the NIDDK advisory groups, or directives
from the U.S. Congress and/or the Administration. This component
also provides a summary overview of the NIDDK's major ongoing initiatives
and is presented to the full NIDDK Advisory Council each September.
Initiatives proposed in the NIDDK Program Plan:
- Build on past accomplishments;
- Reflect emerging scientific needs and opportunities;
- Are responsive to the changing fiscal environment and new Congressional
and Administration directives; and
- Are consistent with the NIDDK's commitment to investigator-initiated
research.
The Program Plan is actually a compilation of the separate annual
planning processes of the NIDDK's three extramural scientific divisions
and reflects an effort on the part of each division to identify
the best scientific opportunities to pursue.
Annual Planning Process of the NIDDK's Extramural Scientific
Operating Divisions
Each of the three extramural divisions employs a range of planning
mechanisms, starting at the programmatic staff level.
Program staff assess the state-of-the-science in their respective
areas by attending and convening scientific meetings, reviewing
their grant portfolios and published literature, and through discussions
with grantees and other individuals and organizations within the
scientific community.
For example, when areas of scientific opportunities are identified
by both the NIDDK and the extramural communities, they are prioritized
through discussions held with program staff and their respective
division directors. Preliminary program initiatives are then discussed
with the division's sub-council of the Institute's National Advisory
Council.
Divisions also seek participation from leading professional societies
and lay organizations that have an interest in the areas of the
division's research portfolio. Input is also solicited from experts
in specific areas through specially created ad hoc advisory
groups. Workshops are another venue through which the NIDDK extramural
divisions seek input into their planning activities. Divisions do
not undertake major initiatives without first seeking input and
advice from these groups.
Benefits of the NIDDK's Planning Process
In addition to being a requirement of the NIH and an expectation
on the part of the U.S. Congress, the NIDDK program planning process:
- Enables the Institute to reply accurately to frequent public
and Federal inquiries regarding its programs, i.e. the state of
the science in a particular field; examples of recent scientific
progress; perceived research needs and opportunities; resource
needs and allocations; and the Institute's approaches for meeting
its responsibilities.
- Serves as a means to aid Institute staff members in keeping
abreast of developments in their areas of responsibility. It is
through this expertise that management responsibilities are coordinated.
- Permits the Institute to be in a position to act in a timely
manner to implement a given program or to stimulate work in a
certain special-emphasis area should the need or opportunity arise
and the funds be made available for that purpose.
- Provides material to justify the value of existing scientific
activities and to be able to identify compelling scientific needs
and opportunities that warrant the allocation of additional resources.
Strengthening the NIDDK's Planning Process
The NIDDK's program planning process is continuously evolving and,
as stated previously, is predicated on wide-ranging and continuous
collaboration between the NIDDK and non-Federal scientists and other
advisors, including the Institute's National Advisory Council and
sub-councils, as well as ad hoc advisory groups to the NIDDK
operating divisions, NIDDK-sponsored workshops and conferences.
Since 1997, the NIDDK has solicited wider input from the Advisory
Council and the broader scientific community in an effort to strengthen
its program planning process. Each of the NIDDK extramural operating
divisions, for example, is now interacting more fully with its respective
communities through a variety of means, ranging from ad hoc
meetings to conference calls.
As a result of the interaction and feedback received from the Advisory
Council and other external advisors, the approach to the Program
Initiative Concepts portion of the Program Plan document has been
changed.
Changes already introduced to strengthen the Program Initiative
Concepts document include:
- Greater linkage between the Program Initiative Concepts and
ongoing initiatives within the NIDDK research portfolio.
- Greater emphasis on the scientific rationale for Concepts and
less emphasis on the "instrument" or mechanism through
which the scientific need and/or opportunity may be pursued or
implemented.
- Linking Concepts to the NIH Director's Areas of Emphasis
In future planning processes linkages will be made between Annual
Program Initiative Concepts and the cross-cutting themes of the
NIDDK Strategic Plan.
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The National Institute of Diabetes and Digestive and Kidney Diseases' Strategic Plan
The National Institute of Diabetes and Digestive and Kidney Diseases'
(NIDDK) Strategic Plan addresses the global challenges and opportunities
facing the NIDDK, and outlines research directions within the Institute's
mission that be should pursued over the next five years. The Plan
represents a collaborative effort, with input coming from NIDDK's
senior scientific management working with the National Advisory
Council, the scientific community at large, lay and professional
organizations, and the public.
During 1999, NIDDK senior management held multiple Working Group
meetings, had discussions with Working Group members, analyzed the
existing NIDDK research portfolio, solicited comments from lay and
professional organizations, and heard public comment. During the
development of the Plan, Working Groups interacted closely with
one another to cross-fertilize ideas among themselves. They also
evaluated current state-of-the-art science in an effort to develop
a comprehensive and scientifically achievable plan.
Working Groups were responsible for identifying and emphasizing
the common, scientific, cross-cutting themes, scientific opportunities,
and research gaps and challenges across the programs and divisions
of the NIDDK. In order to adequately reflect the compelling scientific
opportunities and public health needs identified through this deliberative
process, the Plan has been divided into the following four sections
or themes:
- Genes and Disease
- From the Cell to the Organism: Unraveling the Complexity of
Living Systems
- Prevention and Treatment of Disease: Epidemiology and Clinical
Investigation
- Research Infrastructure
These themes were presented to and broadly endorsed by the NIDDK's
National Advisory Council, the NIDDK research community and the
many lay and professional organizations with an interest in the
research conducted and supported by the NIDDK.
In the sections that follow, each Working Group presents background
information related to its respective theme, and sets forth a series
of objectives; insights related to those objectives; and a series
of implementation strategies for achieving those objectives.
Working groups made every effort to articulate their portion of
the Plan in non-technical language that would be understandable
to a broad public audience. However, given the intensely science-oriented
nature of the research conducted and supported by the Institute,
the Plan does contain some scientific terminology. Therefore, a
glossary of scientific terms and acronyms has been appended.
A summary of the broad and overarching goals, objectives and strategies
of the Institute over the next five years is as follows:
- To promote the health of the American public through scientifically
meritorious basic and clinical biomedical and behavioral efforts
and related programs.
- To develop a sound base of fundamental science on which future
clinical research advances can be built.
- To understand the natural history and processes of diseases
and disorders within the NIDDK mission.
- To gain insight into, and develop more effective treatment
and prevention strategies for, diseases and disorders that disproportionally
affect ethnic groups and other special populations, such as women
and children, so that these health disparities can be reduced
or eliminated.
- To develop effective treatments for the diseases and disorders
within the NIDDK mission and strategies for preventing or delaying
their onset.
- To develop effective means of preventing, delaying or ameliorating
the complications of the diseases and disorders within the NIDDK
mission.
- To develop and apply technologies, innovative research techniques
and methods from which will flow future basic and clinical research
advances and improvements in the health of all Americans.
- To facilitate the continuation of an adequate cadre of basic
and clinical biomedical research investigators through the recruitment
and retention of talented individuals to research training and
research career development programs, with special attention to
minority recruitment and retention programs.
- To promote dissemination and application of research results
emanating from the NIDDK basic and clinical research studies,
through outreach programs, education programs, and other means,
in ways that are culturally appropriate and meaningful to target
audiences.
GENES AND DISEASE
Overall Goal: To strengthen our understanding of the
role of genes in disease in order to improve prevention and
treatment, and ultimately to cure the diseases for which NIDDK
has research responsibility.
BACKGROUND
Opportunities and Challenges
Why Emphasize Genes?
Over the next 5 years, NIDDK's mission--to improve understanding
and ultimately to find better ways to prevent, treat and cure diseases
in its areas of responsibility--will be achieved in part through
intensified study of genes and disease. A major driving force behind
the dramatic scientific opportunities of the next decade, therefore,
will be the information emerging from the Human Genome Project.
Even now, scientists regularly discuss the imminent arrival of the
"post-genomic era," recognizing that within 2 or 3 years,
as the sequence of the entire human genome becomes known, we will
face great opportunities and new challenges.
These opportunities and challenges include:
Determining How Gene Defects Relate to Inherited Diseases
Many diseases "run in families," and every physician knows that
family history tells much about the risk of disease. Understanding
how diseases are inherited and identifying the specific gene or
genes that confer susceptibility are critical to understanding the
diseases and, ultimately, improving prevention and treatment.
Some familial diseases have the relatively simple and predictable
patterns of Mendelian inheritance, named after Gregor Mendel, the
Austrian monk who first described them. We also call these diseases
monogenic, reflecting the fact that, by and large, they are caused
by a defect in a single gene.
The last decade has seen breathtaking progress in identifying underlying
defects in monogenic diseases. In virtually every case, identification
of the genetic defect has intensified research of the disorder and
increased understanding of the mechanisms of disease. These cascading
events are spawning new diagnostic tests, earlier diagnosis and,
in many cases, new therapeutic strategies.
Some familial diseases are quite rare, and sometimes the identified
genetic defects are responsible for only a small portion of cases.
But the known defects provide important clues for all cases. With
the availability of the complete sequence of the human genome, identifying
the genes responsible for monogenic disorders will become faster
and easier.
A second category of familial diseases are polygenic, also sometimes
called "complex traits." Many serious and very common diseases run
in families, but the inheritance pattern suggests that they result
from interactions of several genes, not from a single defect.
Compared to monogenic diseases, identifying defective genes in
polygenic disorders has proven much more difficult. Genes involved
in a few polygenic disorders have been identified, but by-and-large,
this is an area of research that is just beginning. The complete
sequence of the human genome will permit new approaches to understanding
polygenic diseases.
Understanding Gene Function
After identifying a faulty gene, the next--and absolutely critical--step
is to understand the gene function, that is, how the gene works
and how defects in it lead to disease. Modern methods have revolutionized
the process of studying gene function, and investigators have clarified
how mutations disturb the function of many disease genes. Nevertheless,
enormous scientific hurdles remain. Strategies to strengthen studies
of gene function are also a major focus of all parts of this Strategic
Plan.
Determining How Environments Affect Genes
Inheriting a specific gene, alone, does not necessarily mean an
individual will develop a disease. In fact, most chronic diseases
result from interactions among genes, life-style, and environment.
Thus, diet, exercise, stress, and many other environmental factors
influence whether an individual gets a disease and how severe it
will be. But, because genes determine how we respond to diet, environmental
toxins, drugs, and stresses of daily life, what we learn about genes
may also help us deal with these other factors.
Understanding the interplay of these factors--and how people vary
in their responses--may teach us how to promote health better and,
potentially, predict who will be vulnerable to drug side-effects
and who will benefit from diet and other life-style changes.
Understanding How Modifying Genes Affects Disease
Genes do not act alone. Even the "same" genetic disease
can manifest itself differently. For example, some very young children
with cystic fibrosis have a massively debilitating disease, while
others--even those with the same mutation--may be relatively free
of symptoms until late adolescence or early adulthood. Similarly,
polycystic kidney disease may result in early kidney failure in
one family member and no apparent kidney problems in another family
member. This variability suggests that the product of other genes
may alter the function of the primary disease gene; in some instances,
for example, one gene product may be able to substitute for another.
Knowing more about these modifying genes and how they effect disease
has enormous promise as a way to identify new approaches to therapy.
Understanding How Genes Determine the Development of Cells and
Organs
By identifying and understanding genes that control the formation
of healthy specialized cells and organs, we may better understand
what errors lead to disease. Disease processes, even late in life,
often cause reactivation of genetic programs that participated in
early development and organ formation. Genes determine which cells
have the potential to continue to divide and allow regeneration
of organs. We will be better able to harness the body's capacity
to regenerate and heal when we better understand normal development.
Focusing on Strategies to Exploit Genomic Information
Understanding genes, their function, their role in disease and
tissue injury, exploiting information about genes to find new diagnostic
methods and new therapies are themes that recur in all parts of
the NIDDK's Strategic Planning Processes. The focus of this crosscutting
theme--Genes and Disease--focuses particularly on the approaches
to inherited diseases and on strategies to exploit genomic information
to yield critical understanding.
OBJECTIVES
Because genes are important for all aspects of the NIDDK's investigative
portfolio, the Working Group on Genes and Disease emphasized genetic
diseases and genetic investigation, as well as approaches to disease
that rely on systematic application of genomic information.
In formulating the following objectives, the Working Group chose
priority areas that cut across the Institute's disease interest
areas. These objectives are not intended to be all inclusive, and
it is recognized that many important and relevant research projects
will fall outside these priority areas.
A. INHERITED DISEASES
A1. OBJECTIVE: Identify the genetic loci and the underlying
genes that are responsible for the principal diseases in the NIDDK
portfolio, which show familial patterns of susceptibility, both
monogenic and polygenic.
INSIGHT: The last decade has seen breathtaking progress in the
understanding of monogenic disorders. Many of the diseases caused
by a mutation at a single genetic locus are now characterized at
a molecular level. Progress in understanding the complex (or polygenic)
diseases has been much slower, and will be a key challenge for the
next decade.
A2. OBJECTIVE: Identify genetic loci that explain the variable
clinical presentation of certain key monogenic diseases and begin
to clarify how the interaction of several genetic loci can produce
polygenic diseases.
INSIGHT: As discussed previously, a number of genetic diseases
are highly variable in their presentation. Environmental factors
may explain part of this variability. However, work in animal models,
particularly mouse models, has established that secondary modifying
genes can alter the expression of a disease gene or substitute for
its function. In polygenic disorders the interaction of two disease
loci may operate in a similar fashion to that between the primary
gene which causes a monogenic disorder and a modifying locus. Identification
of such modifying genes, both in animal models and in human disease,
is a valuable approach to finding new therapeutic approaches to
diseases and understanding gene interactions.
A3. OBJECTIVE: Improve the precision with which we can characterize
the clinical phenotype of the key diseases in our portfolio, with
the goal of identification of genetically homogenous sub-groups.
INSIGHT: Many of the important complex disorders in areas of NIDDK
interest are extremely heterogenous. Current classification schemes
and diagnostic categories often do not adequately address this heterogeneity.
Systematic collection of patient information and a new generation
of clinical tools--including new molecular methods--may in some
cases lead to recognition of homogeneous sub-groups, sharing genetic
predeterminants. This more precise characterization is expected
to speed genetic investigation.
The informed physician-scientist will be critical for this process.
The Genes and Disease Working Group emphasized the important role
of strengthening clinical investigation for the new scientific opportunities.
A4. OBJECTIVE: For certain key diseases of concern to NIDDK,
clarify the extent of familial aggregation.
INSIGHT: For a number of important diseases the extent of familial
aggregation is still unclear. Careful studies to establish the relative
risk to family members of patients with these disorders is an important
step in determining whether or not genetic approaches will be helpful.
A5. OBJECTIVE: Identify the genetic differences that contribute
to population differences in susceptibility to disease.
INSIGHT: In many cases, the disproportionate burden of disease
experienced by ethnic or racial sub-groups in the population can
be explained by genetic differences. These differences may ultimately
identify therapies of special efficacy in such sub-groups.
A6. OBJECTIVE: Understand the genetic basis of variable responses
to important categories of therapeutic drugs, including genes that
result in susceptibility to drug toxicity.
INSIGHT: Some therapies are very effective for some individuals
and are virtually totally ineffective for others. The ultimate goal
of tailoring the right therapy to each patient will be fostered
by intensified study of the role of genetic variability in determining
the response to therapeutic drugs and the vulnerability to drug
toxicity.
B. GENE PROFILES ALTERED BY DISEASE
B1. OBJECTIVE: Establish for selected major diseases in the
Institute's portfolio the patterns of altered gene expression in
important target tissues.
INSIGHT: Part of the study of genes and disease needs to include
defining the effects of key diseases on the pattern of genes expressed
in damaged tissues. Gene expression profiles have special promise
for a number of reasons. They are likely to: assist in identification
of new therapeutic targets; define candidate genes for studies of
complex traits; and provide new tools for diagnosis and management.
(NOTE: These methods are discussed further in the following section
on strategies to meet our objectives.)
B2. OBJECTIVE: Exploit the potential of gene profiling and other
molecular methods to improve methods for disease identification,
classification, and determination of prognosis.
INSIGHT: Currently, most diagnostic methods use radiographic tests,
biochemical methods or microscopic study of pathological tissue.
The methods of molecular biology and new understanding of the role
of genes in disease are, however, opening up a range of new diagnostic
methods. It will be important to ensure that the potential of these
new methods is fully exploited for diseases within the NIDDK mission.
C. GENE PATHWAYS IN ORGAN DEVELOPMENT
C1. OBJECTIVE: Identify the genetic pathways critical for the
formation of organs in the NIDDK areas of research responsibility,
and understand how these genes work to dictate cell lineage specification.
INSIGHT: Developmental pathways are often reactivated by tissue
injury, and regeneration and healing may use the same genes that
are active when an organ forms. Strengthening Institute programs
in organogenesis, with particular focus on understanding gene pathways
that dictate cell lineage, is considered an important objective
for ultimately harnessing the potential of these pathways.
C2. OBJECTIVE: Use knowledge of these gene pathways to develop
strategies to facilitate healing and regenerative processes and
the maintenance and differentiation of stem cell populations.
INSIGHT: Practical implications of intensified study of developmental
biology include new strategies for cell and tissue engineering,
as well as potential identification of new target molecules for
therapeutic intervention.
D. GENE FUNCTION AND REGULATION
D1. OBJECTIVE: Foster investigation that will clarify molecular
function of key disease genes.
INSIGHT: A number of the objectives developed in this chapter focus
on the identification of disease genes. It is important to reiterate
that identification of a disease-causing gene is just a beginning
that needs to be followed by intensified study of disease mechanism.
(NOTE: Subsequent sections in this Strategic Plan include discussion
of functional studies of genes at the cell and organ levels, and
studies of how genes participate in the injury process.)
D2. OBJECTIVE: Foster investigation that will clarify
fundamental mechanisms of gene regulation by hormonal, dietary and
environmental variables.
INSIGHT: Study of regulation of gene expression is a key area of
strength in our investigative portfolio. Elaborate networks of interacting
proteins, the complexity of which is just beginning to be understood,
regulate gene expression in the cell nucleus. Many new scientific
opportunities exist to untangle these regulatory mechanisms. Intensified
study of the regulation of gene expression is anticipated to yield
new understanding and ultimately to identify new therapies.
IMPLEMENTATION STRATEGIES
Progress toward each of the objectives defined above will most
likely result from the collective achievement of a number of individual
investigative teams supported by the NIDDK's scientific research
portfolio that consists of investigator-initiated grants. The strategy
of funding such grants and making them the core of the Institute's
scientific research portfolio has been highly successful in the
past and should continue.
However, in the process of developing its portion of the NIDDK's
Strategic Plan, the Working Group on Genes and Disease identified
a number of barriers that can limit the capacity of the individual
investigator to make progress toward these objectives.
The proposed implementation strategies that follow recognize these
barriers. Subsequently, a number of the strategies recommend investment
in the development of research resources and research tools that
will enhance the ability of the individual investigator-led teams
to achieve their objectives.
(NOTE: Discussion of implementation strategies did not attempt
to determine the best mechanism for the NIDDK to encourage each
type of effort. It was recognized that in some instances specific
and targeted research solicitations would be appropriate, and in
others educational efforts such as workshops might be the most effective
response.)
A. STRATEGIES TO STRENGTHEN GENETIC STUDIES
The Working Group on Genes and Disease felt the process of identifying
the genetic defects responsible for monogenic disorders has substantial
momentum and current strategies were viewed as having a track record
of success. Vigorous continued support for such efforts was enthusiastically
recommended.
The Working Group also identified a number of barriers to identification
of the genes responsible for polygenic or complex traits, the most
notable being the major scientific difficulty of the undertaking.
Investigators studying polygenic disorders uniformly face resource
limitations, particularly because of the need for large cohorts
of patients, and the costs and difficulty of good clinical phenotype
characterization.
Because of the substantial difficulty and costs of studying polygenic
disorders, the Working Group strongly advised that efforts in this
area need to be carefully targeted. Priority setting should weigh
the public health burden of the disease in question, the extent
to which familial aggregation is clear-cut, and the likelihood of
identification of functionally important genetic pathways.
Implementation strategies to strengthen genetic studies are as
follows:
A1. STRATEGY: Facilitate the development of cooperative
consortia in order to permit large-scale genetic studies, particularly
for polygenic disorders. Create innovative models for cooperative
consortia, in which the advantages of cooperation are secured, but
innovative approaches, particularly for phenotype characterization,
are not discouraged.
A2. STRATEGY: Exploit fully homogeneous populations and
patient sub-groups with monogenic inheritance patterns to reduce
genetic complexity.
A3. STRATEGY: Develop methods to strengthen patient recruitment
into genetic studies and to improve public awareness of the potential
benefits of genetic research.
A4. STRATEGY: Encourage development of innovative analytic
strategies for genetic studies.
A5. STRATEGY: Generate clear expectations for patient
data and DNA sharing in all NIH-funded genetic studies.
A6. STRATEGY: Encourage research that will improve the precision
of phenotypic characterization with the goal of identification of
genetically homogenous sub-groups. Strengthen population-based studies
of certain key NIDDK diseases to improve definition of natural history
and its variability.
B. STRATEGIES FOR SYSTEMATIC ASSESSMENT OF GENETIC INFORMATION
One important strategy to exploit information emerging from the
Human Genome Project is to undertake systematic studies of patterns
of gene expression. The rapidly evolving technology for gene profiling
currently permits assessment of the expression profiles for large
numbers of genes in cultured cells and organs, and it may soon be
feasible to assess gene expression at the level of a single cell
or a few cells. Also under development are methods to assess gene
expression systematically at the protein level.
The techniques show substantial promise to open unexplored and
unanticipated avenues for research. Applied to diseased tissue,
gene expression profiles can identify candidate genes for genetic
studies and target molecules for therapeutic intervention. Applied
to sequences for which the gene function is still unknown, these
methods can identify important new genes and provide important clues
to gene function. Used to study gene transcription, the methods
can establish groups of genes that show coordinate regulation.
The Working Group on Genes and Disease considered it important
to encourage promising applications of these methods and to make
the information from these techniques broadly available.
Implementation strategies for systematic assessment of genetic
information are as follows:
B1. STRATEGY: Use systematic studies of gene expression
in diseased human tissue from patients with polygenic disorders
to identify candidate loci.
B2. STRATEGY: Use systematic studies of gene expression
to characterize stem cell populations and cell lineage specification.
B3. STRATEGY: Characterize animal models of disease and
determine the extent to which gene profiles mimic human disease.
B4. STRATEGY: Ensure--in cooperation with trans-NIH efforts--investment
in technology development for systematic gene expression studies.
B5. STRATEGY: Ensure ready availability of methods and
reagents to NIDDK investigative communities.
C. STRATEGIES FOR DEVELOPING GENETIC MODELS TO STUDY DISEASE
Deciphering the human genome will require a wide range of biological
models and systems, and matching the scientific question to the
right model will be of critical importance. Good choice of animal
models and other model systems can have substantial impact on the
rate of progress in studying disease.
Many fundamental biological processes show extensive evolutionary
conservation, and there are a number of striking examples where
findings from simpler organisms, such a C. elegans, fruit
fly, yeast and zebrafish, have yielded immediately relevant insights
into human disease.
The mouse is emerging as a model for human disease of particular
importance, in part because it is the mammalian model in which both
genetic studies and genome manipulation are most advanced.
Implementation strategies strengthen studies of genes and disease
in animal models are as follows:
C1. STRATEGY: Encourage the development of animal models
that more faithfully replicate human disease processes.
C2. STRATEGY: Use systematic gene expression profiling
to establish relevance of animal models to human disease.
C3. STRATEGY: Encourage the exploitation of a wider range
of model organisms.
C4. STRATEGY: Participate in the development of genomic
and genetic tools for model organisms of particular promise for
the NIDDK areas of science.
C5. STRATEGY: Develop shared molecular tools and reagents
for model organisms important for study of the genetics of disease.
D. STRATEGIES FOR THE EFFECTIVE USE OF INFORMATION TOOLS
It is widely recognized that the provision of certain kinds of
easily accessible, searchable information is dramatically changing
the process of science. The Working Group on Genes and Disease felt
that informatics needed for each investigative community varied
substantially, and that activities in this area needed to be carefully
tailored to scientific need, and well-coordinated with other trans-NIH
efforts.
Implementation strategies for the effective use of information
tools are as follows:
D1. STRATEGY: Develop programs to improve availability of organ-specific
annotated sequence information.
D2. STRATEGY: Develop appropriate informatics tools and databases
for study of the genetic basis of disease.
D3. STRATEGY: Ensure that investigative communities have access
to training in the use of informatics tools.
FROM THE CELL TO THE ORGANISM: UNRAVELING THE
COMPLEXITY OF LIVING SYSTEMS
Overall Goal: To understand the internal workings of
each cell type in isolation, how cells function in the communities
that make up tissues and organs, and how cell function is integrated
in the intact human body so as to better prevent, treat and
cure diseases.
BACKGROUND
The Importance of Studying Cells
To repair and maintain a car a mechanic must understand the function
of each part of the vehicle, how each part connects to form a system
such as the engine, brakes or steering, and how these systems work
together to allow the car to operate. Similarly to prevent, treat
and cure disease, we must understand the make-up, function and interactions
of living cells, tissues and organ systems.
To understand when and how cells are harmed in the course of disease,
we must first understand how healthy cells function and communicate
with each other at the molecular level. Such knowledge is essential
to our ability to identify subtle but crucial molecular changes
in cells and tissues. This knowledge also has implications for early
detection of disease, prediction of disease course, response to
particular therapies, and identification of molecular targets for
development of new therapies.
All cells share common features
Human cells are composed of the same substances (proteins, fats,
carbohydrates, nucleic acids, salts and water) that are found in
all living cells. Many of the more complex molecules within cells,
such as genes and the proteins they encode, occur in what is often
referred to as families, with each protein or gene having a similar
but not identical genetic sequence.
Human cells may contain many members of each family, often with
overlapping functions. This complexity can make it difficult to
tease out the function of individual molecules. Often clarification
of the function of these molecules is easier in simpler organisms,
such as yeast, worms or flies, which generally share at least one
member of each family of proteins found in humans but contain fewer
such family members.
As a consequence of the fundamental similarities in mechanisms
by which all cells operate, keys to understanding function, such
as digestive or kidney function, and diseases such as diabetes,
or liver disease may lie in research in these simpler systems. These
connections between humans and lower life forms must be recognized
and exploited through study of simpler "model organisms"
that are directly relevant to human cells.
Major differences among cell types
Despite the similarities common to all life forms and the principles
underlying cell function, cells vary greatly in size, shape and
function. In each person a single cell, the fertilized egg, gives
rise to hundreds of different cell types. Each cell in the body
contains the same set of genes. If it can be determined how, from
this common cell, the diversity of mature cell types (muscle, fat,
liver, pancreas, intestine, kidney, bladder, blood, bone, thyroid,
etc.) is generated, the secrets needed to regenerate and restore
damaged or destroyed tissues may be unlocked.
From the cell to the organism
In each individual, the fertilized egg, a single cell, gives rise
to all the cell types necessary to form a functioning human being.
Each of these cell types contains an identical set of genes. Human
life depends on the cooperation and specialization of all of these
diverse cell types.
OBJECTIVES
To understand, treat, prevent, and cure diseases, we must understand
the internal workings of each cell type in isolation; how each cell
functions within a community such as tissues and organs; and how
cell communication function is further integrated in the intact
human body. To accomplish these goals the Working Group on From
the Cell to the Organism: Unraveling the Complexity of Living Systems
has delineated the following objectives.
A. CELL STRUCTURE AND ORGANIZATION
The following objectives are critical for understanding cell processes,
such as how hormones generate cell response, how substances are
transported in the body, and how cells metabolize fuel:
A1. OBJECTIVE: To define the mechanisms by which cells interpret
and integrate signals to produce a cellular phenotype, including:
the molecular-structural bases for signal transduction: the structural
components of receptors, channels, pumps, transcription factors,
kinase cascades, and other signal transducers that define cellular
function and confer specificity; the mechanisms by which specificity
of cellular responses is achieved with a common set of signaling
molecules; the interplay and interaction among signal transduction
pathways; the mechanisms by which signals are conveyed to the nucleus
resulting in the regulation of gene expression; and the role of
extracellular, cyto-and nuclear architecture in the regulation of
tissue-specific gene expression.
A2. OBJECTIVE: To define novel components of relevant supramolecular
assemblies and elucidate their interactions and functions.
A3. OBJECTIVE: To understand the molecular mechanisms underlying
assembly, processing, localization, and turnover of macromolecules.
A4. OBJECTIVE: To elucidate the biogenesis and functions of
specialized membrane compartments, such as mitochondria, vesicles,
and lysosomes.
A5. OBJECTIVE: To determine how cells establish polarized domains
and localize supramolecular complexes to modulate their function.
INSIGHT: A membrane surrounds each human cell. This membrane keeps
the cell intact and provides an anchor for channels that open and
close to allow specific molecules to enter and/or leave the cell,
and for receptors, which relay messages between cells and from the
environment to the interior of the cell. Many structures found within
a cell are enclosed in similar membranes, all of which serve the
same functions. These membranes play key roles in allowing cells
to interact with each other, with their environment, and in compartmentalizing
and organizing functions in a cell.
Membranes contain proteins that give each type of cell unique properties.
For example specific cell types have different forms of membrane
proteins that transport sugar into the cell, called glucose transporters.
Uptake of the sugar glucose plays a key role in the regulation of
insulin production in the pancreatic beta cell and further regulates
production, storage and release of sugar by liver, muscle, kidney
and fat cells. Each of these cells has an important role to play
in regulating blood sugar levels and the diverse forms of the glucose
transporters are key in allowing these cells to carry out their
unique metabolic functions.
Membrane proteins also help transmit messages from the environment
to specific cell types, regulating cell function. Cell membranes
also are targets for a large number of drugs and of hormones, which
bind to membrane receptor proteins. These receptors transfer the
hormone signal to the interior of the cell, generating "second
messengers" within the cell that regulate key cellular activities.
For example, blood-forming cells have receptors for erythropoietin
(Epo), a hormone made in the kidney which regulates red blood cell
formation. Too little of this hormone leads to anemia and inadequate
transport of oxygen within the body, causing fatigue and weakness;
too much of this hormone causes excessive blood formation, increasing
an individual's risk for stroke. Therapy with Epo represents one
of the great successes of biotechnology, dramatically improving
the wellbeing of patients with end-stage renal disease.
The 1999 Nobel Prize for Physiology or Medicine was awarded for
the discovery that ''proteins have intrinsic signals that govern
their transport and localization in the cell." The biotechnology
industry has used these signaling mechanisms to manipulate cells
to produce large quantities of insulin, growth hormone, Epo and
other proteins for therapeutic use. This discovery also helps explain
how errors in protein localization--arrangement of proteins within
a cell or membrane--occur and cause disease. Each newly formed protein
must be appropriately processed to its mature, functional form,
and targeted to its correct location within the cell. Cellular proteins
must be properly folded into a complex, three-dimensional structure
that is essential for performing a specific function. Proteins that
are not correctly folded are targeted for destruction. A number
of diseases are due to folding defects in specific proteins. For
example, in cystic fibrosis, deletion of one of 1284 amino acids
in the CFTR protein produces a misfolded protein that is degraded
rather than properly transported to the cell membrane where it normally
functions as a transporter. Understanding the mechanisms by which
proteins are correctly folded and transported could lead to new
approaches for therapy of cystic fibrosis and other diseases.
Within each cell are specialized compartments, walled off by internal
membranes, to form discrete spaces where cellular processes occur.
In mitochondria energy is transferred from sugar to storage as ATP.
Other compartments sort proteins, such as secreted hormones, into
packages addressed for their final destinations. In the lysosomes
and peroxisomes, enzymes break down food and other substances. A
large number of genetic metabolic diseases arise as a consequence
of defects in specific proteins required for activities that occur
in these specialized compartments. For example, in storage diseases
such as Hurler disease, cells and tissues are damaged by massive
accumulation of material in the lysosomes that cannot be digested.
Compartmentalization occurs not only as a result of separation
of activities by cell membranes, but also due to formation of supramolecular
complexes. We know that an elaborate network of control mechanisms
regulates and coordinates these interactions. Unraveling the mechanisms
of molecular recognition leading to formation of these complexes,
and the nature of the cooperative interactions which occur as a
consequence, is essential to understand the mechanisms by which
signaling occurs within cells. For instance, formation of such complexes
is important in insulin signaling and defects in specific components
of the complex may contribute to diabetes.
B. CELL DIFFERENTIATION, GROWTH AND EXPANSION
The following objectives are critical for understanding cell differentiation,
proliferation and death:
B1. OBJECTIVE: To define the characteristics of pluripotent
cells which permit them to progress along a specific developmental
pathway or to maintain a pluripotent state.
B2. OBJECTIVE: To define the function of cell products relevant
to development and differentiation.
B3. OBJECTIVE: To define the mechanisms by which commitment
to a specialized cell type is initiated and maintained.
B4. OBJECTIVE: To define functional correlates of the life cycle
of the cells: for example, the temporal and spatial patterns of
gene expression, which explain cell proliferation, cell death and
control of cell number.
INSIGHT: Every cell in the human body contains the same genes.
During development, cells are programmed so that some genes are
expressed and others are silent. This process is called differentiation
and is responsible for the specialized characteristics that make
one cell a liver cell and another a thyroid cell. The ability to
control differentiation and to identify, isolate and characterize
stem cells holds great potential for therapeutics, particularly
tissue replacement.
Stem cells are undifferentiated cells that can give rise to many
cell types. Totipotential stem cells can give rise to an entire
organism. Pluripotent stem cells can generate all the cell types
of an organism, but not the entire organism. Other types of stem
cell can give rise to a more limited repertoire of differentiated
cells. For example hematologic stem cells can generate all types
of blood and many bone cells. An array of stem cells can now be
isolated from mice and other research animal models and tools are
being developed to identify, characterize and purify these cells.
These cells hold promise for development of therapeutics and replacement
tissues through understanding of control of their differentiation.
Recently, two groups of scientists have succeeded in isolating
and culturing the first human pluripotent stem cell lines. These
cells can give rise to all of the different types of specialized
cells in the body, yet they are not totipotent and thus cannot give
rise to an entire human being. The excitement surrounding this discovery
lies in the ability of these cells to divide and self renew as well
as to commit to become cells with more specialized function, such
as liver, blood, bone or pancreatic beta cells. The use of these
cells for transplantation to replace or repair damaged tissue is
discussed under therapeutic applications, later in this chapter.
To make these applications a reality, fundamental research is needed
to identify the signals that direct the differentiation of a stem
cell and cause it to develop into a specific cell type. Understanding
the cellular decision making process will give us the tools to direct
pluripotent stem cells to become the cells and tissues needed for
transplantation.
It is by the growth and division of cells that organisms are formed.
Cell growth and division is organized into a cycle of events. This
cell cycle is influenced by external regulatory signals. Although
formation of new cells and cell death might appear to be opposing
processes, they are closely coupled. Apoptosis, or programmed cell
death, is a normal consequence of cell proliferation. This cell
suicide mechanism enables control of cell number and eliminates
individual cells that threaten the body's survival. Certain cells
have unique sensors, termed death receptors, on their surface which
recognize signals from outside the cell and trigger cell death.
Survival signals from nearby cells may block this death mechanism.
This communication regulating apoptosis is critical to immune system
function. One type of cell targeted for destruction is that which
recognizes self. A malfunction in elimination of these cells can
lead to an attack on the body's own cells, resulting in autoimmune
disease, such as type 1 diabetes or inflammatory bowel disease.
Cell proliferation and death are closely regulated processes. Mechanisms
to replace worn out cells or make more cells are highly regulated.
While some cells are very short-lived and are continually replaced,
others cannot reproduce and cell death leads to a permanent deficit.
Even small imbalances in cell number can have devastating consequences.
For example, the cells that form and remodel bone are continuously
dying and being replaced by new cells arising from the bone marrow.
Changes in the numbers of these active bone cells due to altered
rates of cell proliferation or cell death can lead to bone loss.
The gastrointestinal tract provides another example of the catastrophic
consequences of altered regulation of cell growth. When the gene
for a transcription factor (which regulates expression of other
genes) was "knocked out" in mice, the animals died shortly
after birth because their intestinal lining cells could not regenerate
and properly absorb food. In contrast, mutations in a gene involved
in the regulation of this same transcription factor causes excessive
cell growth and tumor formation in the colon.
C. ORGANIZATION OF CELLS INTO TISSUES AND ORGANS
The following objectives are important for understanding organization
of cells into tissues and organs:
C1. OBJECTIVE: To define fundamental mechanisms of organogenesis,
including cell migration, differentiation, and cell-matrix and cell-cell
interaction.
C2. OBJECTIVE: To define the mechanisms that promote and restrict
cell growth and proliferation, so that each organ and tissue maintains
only the proper number and size of cells of each type in the proper
spatial distributions during ontogeny, repair and regeneration.
C3. OBJECTIVE: To determine how cell-cell interactions influence
organ function.
INSIGHT: Much remains to be learned about how cells organize to
form tissues and how tissues then form organs. We know that connections
between cells must be precisely ordered. During development, tissues
are formed from cells originating in various parts of the body.
How do migrating cells reach their destination and how do organs
form in particular locations? This process requires that cells selectively
recognize each other and attach. To accomplish this, cells produce
an extracellular matrix, a network of secreted proteins and carbohydrates,
which helps to bind cells together and forms a lattice through which
cells can move. This matrix also serves as a reservoir for hormones
that control cell growth and differentiation and mediates interactions
important for wound healing and tissue repair and regeneration.
Of particular importance for NIDDK is understanding how cells unite
to form epithelial tissues, the sheets of tightly bound cells that
line all the cavities and free surfaces of the body, including the
gastrointestinal tract, bile and pancreatic ducts, kidney collecting
ducts, ureter, bladder and skin. Epithelial tissues have specialized
junctions between cells, forming seals to separate fluids with different
compositions on each side of this barrier. Each type of epithelia
is specialized to accomplish particular functions. The epithelial
cell layer separating the intestinal lumen from the blood is specialized
to permit the absorption of nutrients and their transfer from intestine
to blood. Renal tubular epithelium, the site of damage in acute
renal failure, has important reabsorptive, metabolic and endocrine
functions. Knowledge of its role in maintaining homeostasis is essential
to development of strategies to replace these lost functions and
reduce the high mortality associated with this condition.
The origins of a number of diseases lie in the failure to correctly
generate components of the highly ordered cell architecture of tissues
and organs. We know that proper formation of specific cell types
in the pituitary requires a precise balance among the factors that
regulate gene expression in these cells. From this knowledge has
emerged an understanding of how some forms of dwarfism, as well
as more generalized disorders involving growth and reproductive
and thyroid function, arise from genetic changes which impair the
formation of specific pituitary cells. To uncover the mechanisms
of cyst formation and growth in polycystic kidney disease, the role
of the polycystins, the products of the disease causing genes, in
development and function of the normal kidney must be understood.
D. INTEGRATED CELL FUNCTION AND ENVIRONMENTAL RESPONSE
The following objectives relate to understanding the interaction
of cells and tissues with each other and with their environments:
D1. OBJECTIVE: To understand how signaling processes are integrated
among individual cells and interact to create networks with coherent
and predictable functions.
D2. OBJECTIVE: To understand the integrated combinatorial nature
of local environmental signals.
D3. OBJECTIVE: To understand how specialized cells and tissues
modulate other cells in their local environment.
D4. OBJECTIVE: To define the mechanisms by which specialized
cells and tissues interact with immunocytes and immune mediator
molecules.
D5. OBJECTIVE: To understand the interaction of the cell with
its metabolic environment.
D6. OBJECTIVE: To understand mechanisms by which cells adapt
to unusual environments, such as extremes of pH, oxygen tension,
or osmolarity.
D7. OBJECTIVE: To define the interplay of cells, tissues and
organs to regulate homeostasis of the intact organism, such as regulation
of glucose, salt and mineral concentrations.
INSIGHT: Intercellular signaling is necessary for cooperation between
specialized cell types and for the capacity of specialized tissues
to function in an integrated fashion. This is particularly apparent
in the hypothalamus, a brain region with a critical role in integrating
neural control of the endocrine system and endocrine control of
neural function. Here communication occurs almost exclusively through
chemical messengers; cells influence adjacent cells with their secretions
and signaling pathways connect neighboring regions whose integrated
function is essential for regulation of appetite and thirst, response
to stress, reproductive function, metabolism, and salt and fluid
balance. Understanding the complex interconnections between specialized
hypothalamic cells, which make and respond to key hormones and neurotransmitters
involved in appetite regulation, will provide targets for pharmacologic
approaches to control food intake and weight gain. The hypothalamus
also has a key role in sensing and responding to hypoglycemia. Understanding
the signaling pathways involved is important for prevention and
reversal of hypoglycemia unawareness, a key problem limiting therapy
of people with diabetes.
Understanding the cell signaling pathways involved in maintenance
of tolerance and pathways that trigger immune activation are prerequisites
for the development of new therapies to prevent or reverse autoimmune
diseases and to prevent rejection of transplanted organs and cells.
The molecular signals that govern immune cell communication are
the targets for new approaches to immune modulation. Immune cells
called T cells have one receptor responsible for accurately identifying
a potential target. More recently, these cells were found to have
a second signaling system involving a costimulatory receptor which
activates the T cell once target recognition has occurred. Now a
number of agents have been developed that interfere with this costimulatory
receptor. By blocking the specific immune cells that attack transplanted
tissue, these drugs may be safer and more effective than immunosuppressive
drugs in preventing transplant rejection. This approach to redirecting
the immune system to maintain tolerance may also be useful in restoring
self-tolerance in autoimmune diseases.
Wound healing is a process that involves extensive interaction
of cells and tissues with their local environments. In the area
of a skin ulcer, a network of secreted proteins and carbohydrates,
called the extracellular matrix, fosters interaction of the local
affected cells with blood cells and growth factors secreted locally.
Blood cells infiltrate the wound and attach to the extracellular
matrix where they are transformed into specialized cells to cleanse
the wound, and initiate and propagate new tissue formation. The
extracellular matrix helps with the formation of new blood vessels
needed to sustain the new tissue. Local release of growth factors
stimulates these processes. In diabetes, high blood sugar, reduced
delivery of oxygen and other nutrients due to vascular disease,
and other alterations in the local metabolic environment can impede
this healing process.
Our cells function best in a carefully controlled environment maintained
by a complex system of regulatory networks designed to maintain
key parameters within the narrow range optimal for health. Hormones
are essential to regulate cell function to maintain this internal
environment. For example, calcium concentration is tightly controlled
by hormonal mechanisms. Specialized cells in the parathyroid gland
have a calcium sensor that triggers rapid release of parathyroid
hormone (PTH) in response to any fall in blood calcium levels. PTH
stimulates release of calcium from bone, reabsorption of calcium
from urine, and activation of vitamin D to enhance absorption of
calcium from the intestine. The ensuing rise in calcium then stimulates
mechanisms to shut off a further rise in calcium and inhibit further
PTH release. Similar regulatory mechanisms, involving synergistic
effects of multiple hormones on many organs and tissues, exist to
maintain blood sugar and salt concentrations, fluid balance, blood
pressure and other critical parameters within narrow limits. These
involve coordination of simultaneous responses involving multiple
hormones, counterbalancing influences to fine tune responses, and
mechanisms to terminate the hormone response.
Many drugs affect multiple tissues, with effects on one tissue
conferring benefit, while risks or side effects derive from effects
on another tissue. For example, estrogen replacement therapy is
clearly beneficial in preserving bone mass, yet its effects on the
cardiovascular system, blood clot formation, breast and other tissues
are less well understood. The recent discovery of two separate estrogen
receptors with different tissue distributions and new understanding
of how the estrogen receptor interacts with other signaling molecules
within cells to turn genes on and off have important implications
for development of more selective drugs. These "designer estrogens"
are intended to produce beneficial effects of estrogen in some tissues
and to actually antagonize harmful effects in other tissues. Diverse
effects on different tissues are also seen with thiazolidenediones,
a class of drugs, which activate the nuclear receptors that modulate
gene expression in response to fatty acids and lipid metabolites
and are currently being used as insulin sensitizers in the treatment
of type 2 diabetes. These drugs, originally shown to cause differentiation
of fat cells, were more recently implicated in the formation of
scavenger cells that take up lipids and in the inhibition of apoptosis
in colon cells; recognition of these latter effects stimulated investigation
of their possible effects on atherogenesis and intestinal tumors.
The drug discovery process could be streamlined if cultured cell
lines or other methods were available to determine or predict the
integrated effects of a drug on the many cells and tissues of the
intact organism.
E. THERAPEUTIC APPLICATIONS
The following objectives are important to developing therapeutic
applications based on understanding of cell biology:
E1. OBJECTIVE: To define key molecules and critical pathways
which are essential for specialized cell function and which must
be provided and/or regulated to enable functional replacements for
specialized cells.
E2. OBJECTIVE: To identify key targets for molecular modulation
to promote cell regeneration and repair.
E3. OBJECTIVE: To understand factors that maintain stem cells
and control their commitment, as a precursor to their use for tissue/organ
replacement.
E4. OBJECTIVE: To devise methods to enhance growth and yield
of cells produced and modified for therapeutic purposes.
INSIGHT: The life-saving value of donated kidney, liver, intestine,
pancreas and other organs is well established, yet the number of
people who could benefit from transplantation far outstrips the
number of organs available for transplantation. Pluripotent stem
cells have the potential to serve as a renewable source of replacement
cells and tissues to treat many diseases important to NIDDK. The
Institute is committed to applying insights derived from basic investigations
of cell biology to realize the promise of stem cell therapy as well
as develop better methods of cell and organ transplantation and
methods to stimulate tissue regeneration.
Stem cell biology may have important applications, not only for
transplantation, but also for differentiation therapy using an individual's
own cells. During fetal development, pluripotent stem cells develop
into types of stem cells with more limited capacities to form specialized
cells. For example, hematopoietic stem cells can form all the blood
cells and some bone cells, but not other tissue types. Our bodies
contain many types of stem cells that could be used to repair or
regenerate some tissues. Research is needed to identify cells with
these capacities and to develop methods to stimulate their differentiation
into specialized cells. We know that the human body has the ability
to permit new growth and renewal of liver, intestinal lining, renal
tubule, bone, skin and other cells. We must discover whether this
ability also exists for other critical cell types, such as pancreatic
beta cells, and discover methods to enhance the body's regenerative
capacity.
Cellular engineering is another promising approach to replace vital
functions lost to tissue destruction. Development of such therapies
requires an understanding of the molecular mechanisms underlying
the unique functions of each cell type so that these can be recreated
in the therapeutic cells. For example, if we can define every step
in the process by which the beta cell senses the level of blood
glucose and modulates the secretion of insulin in response to changing
blood glucose, we could attempt to recreate this process in a therapeutic
cell protected from autoimmune destruction. In these therapeutic
cells, genes and regulatory elements would be introduced to provide
the functional components needed to mimic the specialized cell function
to be replaced. Cell engineering may also be a useful approach to
induce tolerance once we know which genes should be introduced to
accomplish this. Yet another application of cell engineering involves
creation of animal models, which mimic human disease processes,
and can be used to test promising therapeutic approaches.
IMPLEMENTATION STRATEGIES
The Working Group From the Cell to the Organism: Unraveling the
Complexity of Living Systems developed the following strategies
accomplish the objectives identified above:
A. CELL STRUCTURE AND ORGANIZATION
A1. STRATEGY: Apply microarray technology and computational
biology to the study of the regulation of gene expression: specifically,
to understand the relationship between strength and duration of
a stimulus and the response of a gene.
A2. STRATEGY: Develop methods to measure very low concentrations
and affinities of molecules in cells.
A3. STRATEGY: Encourage new efforts to use biochemical approaches
to study protein-protein interactions.
A4. STRATEGY: Encourage the use of mass spectroscopy to identify
protein components in macromolecular complexes.
A5. STRATEGY: Encourage new efforts at determining the three
dimensional structure of proteins and macromolecular assemblies,
using methods such as NMR, immuno-electron microscopy and 3D imaging.
A6. STRATEGY: Enhance understanding of dynamic interactions
of macromolecules in living cells, employing methods such as fluorescence
energy transfer.
A7. STRATEGY: Develop new optical methods to study sub-nuclear
organization in the context of living cells.
A8. STRATEGY: Develop in vivo imaging methods to monitor the
organization of molecules in supramolecular complexes and subcellular
organelles and encourage the establishment of functional assays
that reconstitute interactions between such assemblies and organelles.
B. CELL DIFFERENTIATION, GROWTH AND EXPANSION
B1. STRATEGY: Apply information from model organisms to understanding
cell differentiation, proliferation and death in higher vertebrates.
B2. STRATEGY: Develop systematic approaches to study gene expression
patterns during different stages of development and the cell cycle.
B3. STRATEGY: Use the power of computational biology (i.e. pathway
prediction analysis) and comparative genomics to understand functional
integration in cells and tissues.
B4. STRATEGY: Develop techniques for rapid and efficient analysis
of changes in protein expression in whole cells and whole tissues.
B5. STRATEGY: Identify promoters with desirable properties such
as lineage and cell specificity.
B6. STRATEGY: Identify cell lines in which differentiation can
be directed and develop tissue culture methods to study cell differentiation.
C. ORGANIZATION OF CELLS INTO TISSUES AND ORGANS
C1. STRATEGY: Develop in vivo measurements to quantitate and
assess the effect of gene perturbations.
C2. STRATEGY: Utilize model organisms to gain insight into the
roles of single genes that operate in complex systems.
C3. STRATEGY: Develop simple and efficient methods to modulate
gene expression in intact animals or organ culture.
C4. STRATEGY: Produce antibodies to epitopes within specialized
regions of extracellular matrix to define the composition of the
matrix and understand its function.
C5. STRATEGY: Develop optimized, chemically-defined media and
matrices for propagation of cells, tissues and organs.
D. INTEGRATED CELL FUNCTION AND ENVIRONMENTAL RESPONSE
D1. STRATEGY: Understand the molecular mechanisms by which cells
act as sensors.
D2. STRATEGY: Learn how to measure the concentrations of paracrine
factors near or on cells and develop methods to detect single or
small numbers of extracellular molecules in vivo.
D3. STRATEGY: Develop model hormonal environments that incorporate
pulsatility.
D4. STRATEGY: Develop methods to look at the response of an
entire organism to agents that may engender disparate responses
in different tissues.
D5. STRATEGY: Use non-invasive imaging to understand physiologic
functions at an organism level.
D6. STRATEGY: Apply information from model organisms to understanding
function in higher organisms.
D7. STRATEGY: Use the power of computational biology and comparative
genomics to understand the integration and interplay among cells,
tissues, organs and environmental factors, nutrition and toxins
on the organism.
E. INJURY AND REPAIR OF CELLS, TISSUES AND ORGANS
E1. STRATEGY: Analyze the role of the immune system in causing
disease and injury, both in diseases known to be caused by specific
infectious agents, as well as diseases in which the primary cause
is unknown.
E2. STRATEGY: Analyze the basis of tolerance using animal model
systems with state-of-the-art techniques, including transgenic animals
and DNA arrays, that allow for dissection of each component of immune
cells, cytokines, and growth factors.
E3. STRATEGY: Examine the role of hemodynamic factors and ischemia
in injury to cells, tissues and organs, dissecting the steps of
ischemic injury and the process through which hypoxia leads to cell
death.
E4. STRATEGY: Evaluate the mechanisms of repair of epithelial
cell injury.
E5. STRATEGY: Evaluate the mechanisms of regeneration in response
to injury of liver, pancreas, kidney and hormonal organs.
E6. STRATEGY: Evaluate the mechanisms of fibrosis that can result
from different forms of injury, but have an impact on a range of
diseases and conditions.
E7. STRATEGY: Elucidate the impact of behavior on diseases through
the study of preclinical models.
E8. STRATEGY: Study the influence of nutritional factors such
as anti-oxidants in ameliorating damage to cells, tissues, organs
in animal models of disease.
F. THERAPEUTIC APPLICATIONS
F1. STRATEGY: Encourage basic stem cell research.
F2. STRATEGY: Develop novel methods to safely culture and expand
cells without transformation.
F3. STRATEGY: Develop new ways to increase the quantity and
viability of tissues harvested from cadavers and living donors for
transplantation.
F4. STRATEGY: Develop a deeper understanding of immune tolerance
and rejection.
F5. STRATEGY: Explore innovative, less toxic ways of preventing
rejection, such as inducing immune tolerance or cell encapsulation.
F6. STRATEGY: Devise methods and innovative delivery systems
to promote controlled cell and tissue regeneration in patients.
F7. STRATEGY: Identify novel cell components that can serve
as new targets for drug discovery.
F8. STRATEGY: Develop cell systems and animal models of different
types of injury that are appropriate for assessing therapies.
F9. STRATEGY: Develop therapeutic strategies that enhance or
modify immune response to mediate clearance of persistent pathogens
and terminate chronic infections or ameliorate and limit autoimmune
disease.
F10. STRATEGY: Develop improved gene therapy methodologies applicable
to humans.
F11. STRATEGY: Develop transplantation models and apply these
to assess methods of inducing tolerance.
PREVENTION AND TREATMENT OF DISEASE: EPIDEMIOLOGY
AND CLINICAL INVESTIGATION
Overall Goals: (1) To move advances in science and technology
into patient-oriented applications in a timely and efficient
manner; and (2) to develop targeted interventions for diseases
and complications that are tailored to the needs of specific
individuals and populations.
BACKGROUND
Opportunities and Challenges
As stated earlier in this document, the NIDDK has responsibility
for areas of clinical research related to many diseases, including
cystic fibrosis, diabetes, digestive diseases, endocrine disease,
hematologic diseases, inborn errors of metabolism, kidney diseases,
liver diseases, nutrition, and urologic disease.
These diseases affect individuals of all ages, are often chronic
with a long natural history, and may cause significant morbidity
and reduced life expectancy. In addition, they usually require long-term
management, burdensome self-management, and long-term coping by
affected individuals and their families.
Many diseases within the NIDDK's research mission also may have
several elements that affect the natural history of the disease.
For example, there may be genetic, environmental, and behavioral
factors that influence the development of the disease, disease progression,
and final outcomes. There is also considerable variability in an
individual's susceptibility to the effects of the disease, as well
as certain populations that may have increased or decreased risk,
including children, racial and ethnic minorities, women, men, and
the elderly.
Advances in basic and clinical science are leading to a greater
understanding of the causes and mechanisms of these diseases and
their complications. Many new interventions, for example, are available
that have the potential to prevent, cure, or ameliorate the complications
of diseases within the research mission of the NIDDK. Furthermore,
application of new or improved technologies will make it possible
to identify risk factors for disease occurrence and progression,
which will stimulate new research directions.
Expanding the knowledge base of disease through clinical research,
based on advances in basic science and technology, is critical to
develop effective strategies for disease prevention. With greater
knowledge and understanding of the disease processes and their effects
on different individuals and populations, it will be possible to
develop interventions that are specifically targeted to their needs.
OBJECTIVES
The NIDDK conducts clinical research on all aspects of disease
prevention: primary prevention for those who are at risk
for developing disease; secondary prevention for those who
have the disease; and tertiary prevention for those who have
developed complications of the disease. This comprehensive approach
is needed to ensure the best possible outcomes for people who are
at different stages in the disease process.
However, through the Strategic Planning process, NIDDK, working
in collaboration with its National Advisory Council, the scientific
community, and lay and professional organizations, identified several
barriers that impede the development and implementation of new prevention
and treatment strategies for the diseases within the research mission
of the NIDDK. These barriers include research infrastructure; scientific
understanding; and the identification and recruitment of volunteers
to participate in the evaluation of new prevention strategies.
The following objectives are meant to address these barriers in
such a way as to achieve the overall goals of (1) moving advances
in science and technology into patient-oriented applications in
a timely and efficient manner, and (2) developing targeted interventions
for diseases and complications that are tailored to the needs of
specific individuals and populations.
OBJECTIVE: Increase and enhance the research infrastructure
by addressing the issues of manpower shortages and insufficient
information resources.
INSIGHT: At present, there is limited capacity within the research
community to develop and evaluate the many new treatments and prevention
strategies that are currently available. This limitation will increase
as more new approaches to disease treatment and prevention are developed.
For example, there is a manpower shortage because biomedical research
scientists are not choosing careers in clinical research. Those
who do choose careers in clinical research find that there is insufficient
infrastructure to support their research. In addition, there are
insufficient resources in the areas of biostatistics, bioinformatics,
data management, laboratory support for clinical studies, and for
recruitment and retention of research volunteers. As a result of
these limited resources, there are often long delays in planning,
organizing, and implementing clinical trials, and only a few large
trials can be conducted concurrently.
OBJECTIVE: Advance the science knowledge base so as to gain
a better understanding of the natural history of disease based on
more precise characterization.
INSIGHT: Many of the diseases within the NIDDK research mission
are affected by complex interactions between behavior, genetics,
and the environment. These factors, coupled with variability in
individual susceptibility to the disease processes, make the design
and conduct of clinical studies difficult, and impede the development
of targeted interventions for specific populations and individuals.
Thus, there is a need for much better phenotyping and genotyping
of the diseases within the mission of NIDDK, and for better understanding
the natural history of the diseases based on more precise characterization.
OBJECTIVE: Identify, recruit, and retain more research volunteers.
INSIGHT: Evaluation of new prevention and treatment strategies
developed in animal studies must eventually be evaluated in humans.
Because of the unique and complex nature of humans, many prevention
strategies can only be tested in humans. In particular, identification
of potential research volunteers is a major obstacle for the uncommon
or rare diseases within the NIDDK's research mission. A nationwide
or even worldwide recruitment effort is often needed, because no
one particular center has sufficient numbers of patients to participate
in clinical research.
Once potential research volunteers have been identified, there
are significant barriers to their participation in clinical studies
and clinical trials. For example, currently available research methods
are often time-consuming and entail inconvenience and discomfort
that many subjects find unacceptable. The study of self-selected
patients who are willing to undergo the necessary inconvenience
and discomfort limits the generalizability of research findings.
In addition, there are often historical, cultural, and language
barriers that discourage the participation in clinical research,
often of the individuals who would derive the greatest benefit from
the research advances.
Finally, advances in science and technology are encountering significant
ethical, legal, and social barriers to the participation of individuals
in clinical research. These barriers relate to the participation
of children in clinical research, the identification of disease
susceptibility, informed consent, insurability, job discrimination
and job security.
IMPLEMENTATION STRATEGIES
To achieve the objectives stated above, the Working Group on Prevention
and Treatment of Disease; Epidemiology and Clinical Investigation,
developed the following strategies:
A. STRATEGY FOR DEVELOPING CLINICAL RESEARCH INFRASTRUCTURE
The NIDDK believes that the most efficient strategy to build a
stronger clinical research infrastructure is to establish dedicated
clinical research and clinical trial networks in selected areas
of interest. Specific areas will be targeted for development based
on scientific opportunity, disease burden on individuals and society,
and on the need for a multicenter approach to the disease.
The charge to a particular network also will depend on the knowledge
base and scientific opportunity. Thus, networks might be charged
with conducting clinical research in areas of interest, epidemiologic
studies, or clinical trials using state-of-the-art techniques. For
some diseases, pilot and feasibility studies of new interventions
are needed to evaluate and prioritize them for future large-scale
trials. These networks might also conduct clinical trials in rare
and orphan diseases, or where there are major public health questions
that require a large, multicenter study. Collaboration with industry,
rather than competition with industry-sponsored clinical trials,
will be the most efficient utilization of manpower and other resources.
The components of the individual networks will depend on the specific
disease or diseases under study. NIDDK envisions supporting key
research personnel, biostatistics and research coordinating functions,
central laboratories where necessary, and bioinformatics to facilitate
recruitment of individuals into clinical studies and trials. Efficient
functioning of the networks will require mechanisms to assess potential
studies and interventions and prioritize the research agenda. Funding
for pilot and feasibility studies will be provided in specific instances
to facilitate timely evaluation of new interventions.
B. STRATEGY FOR DEVELOPING BETTER METHODS FOR STUDYING NORMAL
AND DISEASE PROCESSES IN HUMANS
NIDDK will support research to develop new or improved methods
for studying normal and disease processes in humans. The development
of non-invasive or minimally invasive methods is viewed as essential
to increase the science knowledge base, and to encourage participation
of research volunteers. Better processes are needed to assess organ
size and function, pathologic processes, and physiology. Better
methods are also needed for screening, diagnosis, and staging of
many diseases within the mission of NIDDK. New or improved methods
for studying human behavior and its role in disease processes are
also needed. Methods are also needed to predict progression of disease.
Surrogate measures of disease outcomes are needed to shorten the
duration of clinical trials and to allow evaluation of a greater
number of interventions concurrently.
C. STRATEGY FOR DEFINING DISEASES MORE PRECISELY
With the development of clinical research infrastructure and new
or improved methods for studying normal human functions and disease,
it will be possible to precisely define the diseases within the
research mission of the NIDDK.
Precise phenotypic definition of disease is a critical first step
in discovering the genetic factors that underlie the disease. Subsequently,
the NIDDK will support research to phenotype diseases of interest,
including biochemical, physiologic, histologic, anatomic, behavioral,
and sociodemographic measures. Close collaboration between clinical
researchers and geneticists will be encouraged and supported. Once
the genetic factors are discovered, newly emerging array technology
will make it possible to precisely genotype individuals within the
population. Genotyping, along with precise phenotyping, will lead
to the design of better clinical studies and clinical trials of
targeted interventions that are tailored for specific disease processes.
D. STRATEGY FOR APPLYING STATE-OF-THE-ART METHODS
With the development of the clinical research infrastructure, new
or improved methods for studying normal function and disease, and
more precise phenotyping and genotyping, it will be possible to
increase understanding of the diseases within the NIDDK's research
mission.
The NIDDK will support research to identify the factors accounting
for health disparities among different populations and the development
of targeted interventions tailored to the needs of specific populations.
The NIDDK also will support research that defines the role of environmental
factors in disease, including drugs, toxins, viruses and other infectious
agents, behavior, stress, and nutrition. With an increase in the
knowledge base it will then be possible to develop targeted intervention
for minority populations, children, men, women, and the elderly.
E. STRATEGY FOR ADDRESSING THE ETHICAL, LEGAL, AND SOCIAL
BARRIERS TO CLINICAL RESEARCH
The ability to precisely phenotype and genotype individuals at
risk for, and with disease requires careful consideration of the
potential risks to the individual. These include the risks of the
research itself, particularly in children, and the threats to insurability
and job security that discovery of disease susceptibility may entail.
Psychosocial effects resulting from the discovery of disease susceptibility
may be significant. Research is needed to understand these effects,
and to develop management strategies.
The NIDDK will support research in these areas, and will work with
the scientific and lay communities to address these ethical, legal,
and social barriers to clinical research on disease prevention and
treatment.
F. STRATEGY FOR DEVELOPING AND INVESTIGATING NEW APPROACHES
TO DISEASE PREVENTION AND TREATMENT
Advances in basic and clinical research and technology will make
it possible to develop new approaches to disease prevention and
treatment.
The NIDDK will support research on new therapeutic approaches,
including new approaches to changing lifestyle and behavior, and
new or improved treatments such as pharmacotherapy, cellular therapy,
transplantation, immune modulation, and gene therapy.
The NIDDK also will encourage and support research on the application
of engineering and bioengineering technologies to disease prevention
and treatment. Translational research will ultimately be required
for successful implementation of new therapeutic approaches into
practice, and will also be encouraged and supported.
Finally, as better treatments and interventions are discovered,
it will be important to understand their effects on cognitive function,
family function, psychiatric disorders, and quality-of-life.
RESEARCH INFRASTRUCTURE
Overall Goals: (1) To attract the best scientific talent
within the research mission of the National Institute of Diabetes
and Digestive and Kidney Diseases; and (2) to retain talented
researchers over the full course of their investigative careers
(3) and to improve the condition and availability of the research
resources and research tools needed to enhance the conduct research
within the scope of the NIDDK mission.
BACKGROUND
Successful research programs depend upon ideas, technology, appropriately
trained individuals to perform the research and the infrastructure
to conduct the research. The availability and condition of biomedical
research space, in turn, affects the scope and quality of the research
conducted by the research organizations supported by the NIDDK.
Common themes identified by all the Working Groups relating to this
section of the Plan include the need for improved research infrastructure
and capacity, including the need to attract and retain talented
investigative researchers, recruit more volunteers to participate
in the evaluation of new disease-prevention treatments, increase
the number of model systems for our studies, and make data more
accessible to a wider audience through the use of new bioinformatics
technologies.
OBJECTIVES
TRAINING AND CAREER DEVELOPMENT
Currently, the NIDDK supports a full spectrum of research training
and research career development awards. More than 700 individuals
pursue pre- and post-doctoral training under the National Research
Service Act, and approximately 250 individuals pursue more advanced,
mentored research experiences supported by various research career
development awards. This support program is continuously monitored
by the NIDDK program staff and by the NIDDK Advisory Council to
ensure that awards are properly focused on the needs of the scientific
community and that their terms encourage the most talented minds
to train in the areas supported by NIDDK.
The half-life of an investigator receiving support from NIH as
a Principal Investigator, however, is approximately 6 years. This
is an incredibly short time considering the many long, expensive
years that are necessary to prepare an investigator for independent
research.
For the NIDDK to achieve its research objectives will greatly depend
on its ability to develop a cadre of bright, well-trained, and highly
motivated investigators. To ensure that such a cadre of scientists
are ready and able to exploit the opportunities detailed in the
NIDDK's five-year Strategic Plan, the Institute must commit a substantial
portion of its available resources to attracting the best scientific
talent to health problems within the research mission of the Institute.
It must also work to retain talented individuals in research over
the full course of their investigative careers.
To these ends, the Working Group on Research Infrastructure developed
the following objectives. These objectives are cross-cutting and
apply to all research program areas of the NIDDK:
A1. OBJECTIVE: Encourage physician-scientists to select careers
in biomedical research, and provide them with opportunities for
lifelong careers.
INSIGHT: In December 1997, the NIH Director's Panel on Clinical
Research characterized the present state of clinical research as
follows:
"At first glance, it seems impossible to believe that a crisis
in clinical research is at hand because a career in clinical research
today would appear more rewarding than ever. Advances in molecular
medicine are providing enormous scientific opportunities. Never
before has the bench-to-bedside interface been more exciting and
productive. Never before have clinical trials been more promising
as new products of the genetic revolution flow from pharmaceutical
and biotechnical companies. The era of managed care, while challenging
in the extreme, has also opened opportunities for outcomes analyses
and epidemiology that would never have occurred in the absence of
a demand for a more quantitative approach to the results of medical
care. Yet this Panel has gathered data that show that the ratio
of M.D. to Ph.D. applicants for NIH support has progressively fallen
over the past thirty years even though success rates for the two
types of applicants are similar. Importantly, the absolute number
of M.D. applicants has fallen further in the past three years. Furthermore,
M.D.s who fail to achieve fundable priority scores from study sections
following their initial applications are less likely to reapply
than Ph.D.s. This represents a dispirited attitude among M..D. faculty
members that bodes ill for the future of academic medicine and the
public's health. The sense of excitement, opportunity and determination
that should permeate the field is compromised by financial and career
anxieties."
The Panel made the following recommendations for improving the
training of clinical investigators:
- The NIH should initiate training programs that will enhance
the attractiveness of careers in clinical research to medical
students.
- The NIH should improve the quality of training for clinical
researchers by requiring grantee organizations to provide formal
training experiences in clinical research and careful mentoring
by experienced clinical investigators.
- The NIH should initiate substantial new support mechanisms for
young and mid-term clinical investigators, if possible in collaboration
with the private sector.
- A loan repayment program for clinical investigators should be
instituted.
Since the publication of the NIH Director's Panel on Clinical Research
report, the NIH and the NIDDK have responded to several of these
recommendations.
- The NIH initiated three new targeted awards. The K23 award supports
training of new investigators in patient oriented research, the
K24 award offers similar support for mid-career clinical investigators,
and the K30 award offers support to institutions for the development
and implementation of curricula related to patient oriented research.
The NIDDK supports all three of these awards.
- In FY 1999, the NIH significantly raised the stipends offered
under National Research Service Act (NRSA) awards.
- Similarly, the NIDDK has upgraded the attractiveness of its
mainstay career development award, the K08, by raising the maximum
salary compensation to a maximum of $75,000. The NIDDK also offers
K08 holders the opportunity to compete for small grants, to be
held along with their K08s, to allow them to initiate a research
program of significant proportions during the last two years of
their career awards.
While these awards and improvements are too new to be evaluated
at this time, they have drawn impressive numbers of well-qualified
applicants, and the NIDDK has significantly increased the numbers
of career development awards it supports.
A2. OBJECTIVE: Increase the numbers of well-trained investigators
and support staff capable of conducting research to eliminate the
health disparities in all segments of the population.
INSIGHT: Minority groups in the U.S. suffer disproportionately
from many of the diseases that are within the NIDDK's research mission.
For example, the prevalence of type 2 diabetes in African Americans
is approximately 70 percent higher than in whites, and the prevalence
in Hispanics is nearly double that of whites. The Pima Indians of
Arizona have the highest known prevalence of diabetes in the world.
Despite these statistics, minority groups have not been adequately
represented in many research studies, and culturally sensitive approaches
are needed to design appropriate clinical studies of the health
problems of these populations and to encourage minority group participation
in them.
The NIDDK has developed a multi-faceted program targeting the reduction
or elimination of disparities in health status among population
groups, and it is developing interventions focused on the prevention
and treatment of specific diseases in particular subpopulations.
For example, the Institute is currently carrying out the Diabetes
Prevention Program, a randomized clinical trial to evaluate the
preventative effect of programs for weight loss and exercise on
the onset of type 2 diabetes mellitus in high risk populations.
Of the subjects enrolled in this study, approximately 50 percent
are members of minority groups disproportionately affected by this
disease.
Unfortunately, despite the many programs funded by the NIDDK to
reduce or eliminate health disparities and to increase the numbers
of investigators with special interests in this area (many of them
members of the minority groups themselves), the number of such investigators
remains very small and may be decreasing as a proportion of the
overall biomedical research workforce. This must be remedied immediately,
and the NIDDK must find ways to increase the numbers of well-trained
investigators dedicated to addressing and eliminating health disparities
among groups in the U.S. population.
A3. OBJECTIVE: Increase the numbers of investigators who are
members of groups that are underrepresented in biomedical science.
INSIGHT: The NIH recognizes the need to increase the number of
underrepresented minority scientists participating in biomedical
and behavioral research as a means of addressing a potential research
labor shortage in the twenty-first century. As of 1992, underrepresented
minorities constituted only 4.5 percent of the postdoctoral fellows
in the life sciences and less than 2.7 percent of the principal
investigators of NIH research grants. Currently, the American Association
of Medical Colleges estimates that only 2.8 percent of the medical
school faculty members in the U.S. are African American and 3.1
percent are Hispanic.
While the NIDDK has a multi-faceted program of support to encourage
underrepresented minority group members to enter the scientific
workforce in its areas of responsibility, more must be done in this
regard.
A4. OBJECTIVE: Develop programs to encourage the interest of
investigators from outside traditional biology in problems related
to the NIDDK's areas of responsibility, including materials scientists,
physicists, mathematicians, bioengineers.
INSIGHT: Many of today's biological problems are too complex to
be solved by biologists alone. Therefore, research partnerships
across many disciplines are needed, including physics, mathematics,
chemistry, computer science, engineering, and bioinformatics. The
creativity of interdisciplinary teams is resulting new basic biologic
understanding, novel products and new technologies. The NIDDK is
undertaking a number of initiatives intended to foster such partnerships.
For example, the NIDDK has an initiative to stimulate research on
the development of techniques or reagents leading to the ability
to image pancreatic beta cells in vivo. Information gained
from such projects will contribute to the development of a clinical
exam that can be used for monitoring disease progress in diabetes,
as well as patient response to certain therapies. Another initiative
is intended to stimulate research on the development of imaging
methods to assess cyst growth and provide markers of disease progression
for polycystic kidney disease. In both initiatives, because of the
highly specialized nature of the work, imaging experts are encouraged
to collaborate with cell biologists, chemists, engineers, and clinicians.
A5. OBJECTIVE: Ensure that entry into the competition for research
funding is facilitated for new investigators.
INSIGHT: Although it is important to offer support to trainees
at all stages of their development, a crucial test of the entire
process is whether they can make the transition from mentored to
independent investigator status.
A6. OBJECTIVE: Develop mechanisms for providing focused training
programs for new and experienced investigators in new methods and
technologies.
INSIGHT: The tremendous acceleration in pace of scientific discovery
over the last decade, coupled with development of many new high-throughput
technologies, has created an era of unparalleled opportunity to
uncover the causes of disease and identify effective therapies.
For example, the recent development of genome-wide expression profiling
(chip, microarray or Serial Analysis of Gene Expression [SAGE] technologies)
enables a comprehensive high-throughput screening of the effects
of an insult (genetic, physiologic, pathologic, etc.) on gene expression
in tissues and specific cell populations of interest.
These techniques may aid in determining the function of a newly
discovered gene or discovering new biomarkers and therapeutics for
patients with disease. Many investigators with on-going research
programs want to integrate this and other emerging technologies
into their research. However, acquiring the skills to bring a given
technology into a laboratory can be a significant barrier to its
productive use.
IMPLEMENTATION STRATEGIES
The Working Group on Research Infrastructure identified several
barriers to achieving the objectives stated above. Top among those
barriers is inadequate funding. For patient-oriented research, in
particular, the funds available for clinical research are inadequate
to support the number of investigators needed. Also, there are too
few clinical studies and trials in the NIDDK's areas of interest
to provide continuous funding opportunities for investigators.
The Working Group on Research Infrastructure, therefore, believes
that the only long-term solution is for the NIDDK to invest more
dollars in clinical research to provide the funding necessary to
recruit, train and retain talented research investigators. To that
end, the Working Group set forth the following strategies:
A1. STRATEGY: To give trainees intensive exposure to the broad
scientific concepts underlying their chosen fields of interest in
an effort to motivate them to remain in active research for their
entire career. Often coordinated programs that mix didactic and
laboratory experiences can best achieve this over the course of
several years.
A2. STRATEGY: To expand patient-oriented research on health
disparities in all segments of the population, thereby recruiting
and training a cadre of investigators and support staff capable
of attracting volunteers from minority populations.
A3. STRATEGY: To identify talented young people early in their
educational careers who are members of underrepresented groups and
nurtured them throughout their education, both intellectually and
financially. This can be accomplished through opportunities for
clinical research, including pilot grants, new and innovative approaches
, and given every opportunity to develop the interests and skills
required for a career in research. The Institute must seek out and
remove barriers at any and all stages in the career tracks of such
individuals.
A4. STRATEGY: To advocate for more favorable paylines, with
special emphasis and high priority in order to encourage the interest
of investigators from outside traditional biology in problems related
to the NIDDK's areas of responsibility, including material scientists,
physicists, mathematicians, bioengineers.
A5. STRATEGY: To establish a task force or working group to
address ways to aid new investigators to establish their own, independent
research programs. The NIDDK already is committed to monitoring
the numbers of new, first-time investigators receiving research
grants to help ensure that their numbers do not decline.
A6. STRATEGY: To identify emerging new technologies at an early
stage and ensure that access to them by NIDDK-supported investigators
is facilitated by supporting research training opportunities that
are timely and appropriate.
OBJECTIVES
INFRASTRUCTURAL NEEDS
A. ANIMAL MODELS
OBJECTIVE: Identify/establish and characterize accurate
animal models for the study of diseases within the Institute's portfolio.
INSIGHT: Over the past few ears, tremendous progress has been made
in developing new animal models for the study of disease. These
models have led to important new insights into the mechanisms which
lead to the development of certain diseases, as well as insights
into the mechanisms of disease progression. However, opportunities
for greater progress has been limited by numerous factors, including
the expense associated with such studies, the technologies required
to study and characterize animal models are limited, and not all
aspects of a given disease may be accurately mimicked in a particular
animal model.
B. NEW TECHNOLOGIES
B1. OBJECTIVE: Identify new technologies critical to the advancement
of the NIDDK research effort.
B2. OBJECTIVE: Establish new mechanisms for the development
and shared use of novel technologies needed by the researchers supported
by the NIDDK.
INSIGHT: There have been major advances in a variety of new technologies
capable of influencing positively the research conducted and supported
by the NIDDK. Application of these technologies is often limited
due to the high costs associated with such technologies and by control
of the technology by industry. For example, DNA chips and other
high through-put screening technologies could greatly enhance efforts
to identify the genes responsible for many of the diseases within
the research mission of the NIDDK. Development of the specialized
chips for such purposes has substantial costs, often beyond those
of an academic investigator, and often requires the transfer of
intellectual property rights. In some cases, a technology required
to solve a particular problem, or question posed by an investigator,
may not exist.
C. BIOINFORMATICS
OBJECTIVE: Develop mechanisms for the generation and shared
use of databases housing certain kinds of information generated
by the NIDDK investigative community.
INSIGHT: In order to study complex diseases, it is necessary to
integrate enormous amounts of information. For example, a major
outcome of the progress in obtaining genomic sequences from vertebrate
and invertebrate organisms is the ability to elucidate gene function(s).
A direct corollary is the ability to identify particular disease
gene. With the accumulation of large amounts of data has come the
development of relational databases devoted to providing a curated
source of information about genes, including sequences, mutations,
protein products, and relationship to genes from other organisms.
The development of databases that relate structure with function
and provide interactive links to proteins with their sequences has
opened up the prospect for making rapid progress in understanding
gene function and the development of a disease. This revolution
in bioinformatics has permitted investigators to create databases
in which information on a gene, or its expressed protein, can be
sorted and stored in numerous ways, such as by family, function
or relationship to a particular pathway. Thus it becomes possible
to fully catalog a given protein, gene, tissue or organism, with
links to anatomy function, and disease.
D. CLINICAL RESEARCH NEEDS
*Note: Objectives may be overlapping and similar to those objective
outlined in the Prevention and Treatment Section.
D1. OBJECTIVE: Increase and enhance the clinical research capacity
of the NIDDK investigative community.
D2. OBJECTIVE: Assist the NIDDK investigative community to conduct
clinical research to improve the quality of life for those afflicted
with disease, especially ethnic and racial minorities.
D3. OBJECTIVE: Position the NIDDK investigative community to
compete successfully for clinical research support.
D4. OBJECTIVE: Identify, recruit and retain more research volunteers.
INSIGHT: As discussed in previous sections, clinical research represents
the critical interface between the bench and the bedside, with information
flowing in both directions. At present, many types of clinical research
are limited due to the costs associated with conducting this type
of research, lack of training and expertise of investigators, and
difficulty in establishing the needs for bench to bedside transition.
In addition, identification and recruitment of potential research
volunteers is often a major obstacle. Moreover, once these individuals
have been identified, there are sometimes barriers to their retention
in clinical research studies.
IMPLEMENTATION STRATEGIES
A. STRATEGIES TO STRENGTHEN CONDUCT OF RESEARCH ON ANIMAL
MODELS
The Working Groups have identified the following strategies to
strengthen the conduct of research on animal models:
A1. STRATEGY: Ensure investment for research on small and large
animal models.
A2. STRATEGY: Encourage the development of animal models that
more faithfully mimic human disease processes.
A3. STRATEGY: Establish mechanisms, such as innovative models
for cooperative consortia, for facilitating specialized centers
to house, breed and characterize genetically modified animals.
A4. STRATEGY: Encourage development of new methods for characterization
of animal models to determine the extent to which they mimic human
disease.
A5. STRATEGY: Generate mechanisms for storing and sharing information
generated from the study of animal models.
B. STRATEGIES FOR THE EFFECTIVE DEVELOPMENT AND SHARED USE
OF NOVEL TECHNOLOGIES
The Working Groups have identified the following strategies:
B1. STRATEGY: Ensure--in cooperation with trans-NIH efforts--investment
in technology development.
B2. STRATEGY: Generate clear expectations for shared use of
all novel technologies developed by the NIDDK investigative community.
C. STRATEGIES FOR THE EFFECTIVE DEVELOPMENT AND SHARED USE
OF DATABASES
In addition to the strategies relevant to bioinformatics discussed
in previous sections, the Working Groups have identified the following
strategies:
C1. STRATEGY: Develop programs to improve availability of annotated
sequence information.
C2. STRATEGY: Develop appropriate informatics tools and databases.
C3. STRATEGY: Ensure that investigative communities have access
to training in the development and use of informatic tools.
D. STRATEGIES TO ENHANCE CLINICAL RESEARCH
Strategies to enhance clinical research infrastructure were also
discussed in the Prevention and Treatment of Disease section, and
may therefore appear more than once.
D1. STRATEGY: Extend to the NIDDK investigative community expertise
in clinical trial design and analysis found within the Institute.
D2. STRATEGY: Ensure fair and effective reviews of extramural
applications for support of clinical research.
D3. STRATEGY: Enhance partnerships with academic
health centers, foundations, and the pharmaceutical and managed
care industries to increase clinical research.
D4. STRATEGY: Expand interactions with NIDDK-supported Centers
of Excellence, as well as NIH-supported General Clinical Research
Centers.
D5. STRATEGY: Expand the use of telemedicine and other information
technologies to link the research communities.
D6. STRATEGY: Enhance dissemination of information to the public
on the importance and results of clinical research.
D7. STRATEGY: Enhance current on-line directories to identify
clinical studies conducted and supported by the NIH.
SIDEBARS
RESEARCH INFRASTRUCTURE
BIOINFORMATICS
Recent advances in molecular biology, coupled with recent advances
in the technologies used to generate, analyze, and store data, have
allowed for the sequencing of large portions of the genomes of several
species. To understand the function of newly identified genes, individual
scientists generally focus on specific molecules, signaling pathways,
cells, tissues, or organs. Ultimately, however, all of this information
must be combined to form a comprehensive picture of normal cellular
activities and how they are altered in disease states. Increasingly,
the tools of information science are being used to facilitate the
careful storage, organization, and indexing of collected data necessary
for this integration. The emerging filed of study is referred to
as bioinformatics.
Bioinformatics deals with tasks such as creation and maintenance
of biological databases, such as nucleic acid and proteins sequence,
three dimensional protein structures, and characteristics of animal
models, as well as developing an interface whereby investigators
can both access existing information and submit new entries. The
actual process of analyzing sequence information is referred to
as computational biology. This process involves multiple steps,
including the identification of a gene and the DNA sequence; predicting
the structure and function of the protein produced by the gene;
clustering of these proteins into "families" of related
nucleic acid sequences; and aligning similar proteins based on their
DNA sequence to study evolutionary relationships.
The NIDDK is undertaking, or has planned for the near future, initiatives
to obtain genomic and functional information on a spectrum of genes
and their expressed protein products in a number of disease areas
within the NIDDK research mission. For example, the NIDDK has taken
the lead on a trans-NIH initiative to map the zebrafish genome.
The zebrafish, because of its short reproductive cycle and its transparent
and easily accessible embryos, has recently emerged as an important
system for studying events during embryonic development. This system
has broad applicability to many of the NIDDK research programs,
as well as to other Institutes at the NIH.
Goals of the planned Diabetes Genome Anatomy Project (DGAP) are
to identify and characterize all the genes implicated in both type
1 and type 2 diabetes and its complications, followed by complete
characterization of the gene products. Emphasis will be placed on
using the information generated to develop new approaches to diagnostics
and therapeutics and to better understand the diabetes disease process.
An important component of each of these initiatives is the development
of an integrated database to collectively house all information
generated. For example, data will be collected and stored on newly
identified genes, expressed protein products, and the position of
genes in the maps of whole genomes. Each database will be open and
easily accessible to the research community, as well as interactive
so that input from the community may be obtained and incorporated
via frequent updates. External advisors from the user communities,
as well as from the broader bioinformatics and genomics communities,
will be consulted to provide constant input and advice. Ultimately,
it is the hope of the NIDDK that such databases will provide a resource
for investigators for use in the development of new research assays,
for identification of potential therapeutic targets relevant to
the many diseases within our research mission, provide points for
departure for new research studies, and expedite research progress
by disseminating newly emerging information as it develops.
MOUSE MODELS FOR THE STUDY OF HUMAN DISEASE
Animal models provide an essential tool for understanding health
and disease in humans and for evaluating potential interventions
and therapeutics. Animal models make it possible to conduct studies
at the molecular, cellular, and tissue level that would not be possible
in humans, and can help answer questions raised by human studies.
The mouse is an excellent laboratory model for the study of normal
cell function and can provide excellent models of human disease.
Mice and humans share many of the same fundamental biological and
behavioral processes and have extensive similarities at the molecular,
cellular and tissue levels. Mice are also readily susceptible to
genetic manipulation. Therefore, mice are expected to prove particularly
useful for dissecting the interactions involved in complex genetic
traits, where gene action is modified by the behavior of other genes
or by environmental factors. Learning the full genetic make-up of
the mouse will enable the comparison of genetic material among mouse,
humans and other species. This will greatly expedite advances in
many avenues of research, including the discovery of new genes,
the assessment of predisposition to a particular disease, predicting
responses to environmental agents and drugs, and designing new interventions
and therapeutics.
Program Initiatives
The NIDDK is participating in a number of strategies to exploit
fully mouse models in order to accelerate the emergence of new understandings
in health and disease. For example, the NIDDK is participating in
the Trans-NIH Mouse Initiative, launched in October 1999. The goal
of this initiative is to decipher the full genome, or genetic makeup,
of the mouse by mapping the mouse's 21 chromosomes and sequencing
the DNA in the mouse genome.
Another initiative will target mouse models of kidney disease and
will invite investigators with expertise in many areas to form a
consortium to accelerate the pace at which accurate and reproducible
models of kidney disease are developed and made available to the
research community. Polycystic kidney disease and kidney disease
of diabetes mellitus will be areas of special focus. Through the
formation of a consortium, investigators will have access to resources,
information, technologies, ideas, and expertise usually beyond the
scope of any one researcher or research team. As researchers develop
and validate models, the NIDDK will provide mechanisms to disseminate
the models and data collected to the research community.
A parallel initiative will solicit applications to establish national
centers for the purpose of fully characterizing other models useful
for understanding diabetes, its complications, obesity, and other
related metabolic diseases and conditions. In some animal models,
a gene (or genes) is "knocked out" so that researchers
can study what happens in its absence and how this gene may contribute
to or inhibit disease. These facilities would provide a range of
standardized procedures to characterize the physiologic, anatomic,
or pathologic alterations that may occur in these, as well as other
types of models. This type of analysis is referred to as phenotyping.
Another initiative will encourage the development of commercially
available miniaturized assays to measure metabolic and physiologic
function. These specialized assays would be for use in the characterization
of genetically engineered mouse models, or for use in very small
volumes of human tissues.
Research Advances
The NIDDK also reported a number of research advances this year
that demonstrate the importance of mouse models in defining and
treating diseases within the NIDDK research mission. For example,
in an effort to dissect out the role of tissue specific insulin
signals in the development of diabetes, NIDDK investigators have
succeeded in generating a mouse model in which the insulin receptor
from pancreatic beta cells is deleted. Animals lacking these receptors
demonstrate a defect early in insulin secretion, and as they age,
they have a progressive inability to respond to glucose. By six
months of age, they are glucose intolerant, a major feature of type
2 diabetes in humans. Insulin levels in the pancreas also seem to
decline with age in this model, although agents other than glucose
seem to be able to stimulate normal release of insulin. This progressive
loss of insulin secretion in response to glucose, but not to other
agents, is another hallmark of progression to type 2 diabetes in
humans. This work points to receptors on the beta cell as important
sites where impairment of insulin signaling can lead to pancreatic
dysfunction and to the development of diabetes.
NIDDK intramural researchers have demonstrated the prevention of
lysosomal storage in a mouse model of Tay Sachs, a disease in which
there is abnormal accumulation of a specific type of lipid in cells,
resulting in organ and brain damage. The agent tested in this mouse
model acts by blocking a particular step in the synthesis of glucose-based
lipids and could potentially be used to treat all storage diseases
with defects in the degradation of these lipids. To further test
this theory, investigators then created a mouse model of substrate
deprivation for another lipid storage disease. This model had simultaneous
defects in synthesis and degradation of the lipid, mimicking the
effect of the agent described above. These mice no longer accumulated
the lipid, had a much longer lifespan, and had improved neurologic
function, demonstrating the effectiveness of such a treatment.
The NIDDK supports a number of other individual projects that directly
involve the derivation or study of mice that develop specific diseases.
The Institute is committed to supporting in the future coordinated,
collaborative efforts to produce highly accurate mouse models of
human diseases within its research mission. The NIDDK is encouraging
studies for the early design, derivation, characterization, and
validation phases of model building, and will ensure that the models
and the data relevant to them are readily available to the research
community for further investigation or application.
CRITICAL TECHNOLOGIES
The tremendous acceleration in the pace of scientific discovery
over the last decade, coupled with development of many new high-throughput
technologies, has created an era of unparalleled opportunity to
uncover the causes of disease and identify effective therapies.
In particular, the Human Genome Project effort has generated an
explosion of data and potential tools that will aid research in
virtually all fields of medicine. The recent development of genome-wide
expression profiling allows for a comprehensive high-throughput
screening of the effects of an insult, whether it be genetic or
environmental, on gene expression in tissues and specific cell populations.
These techniques may aid in determining the function of a newly
discovered gene, discovering new ways to identify individuals at
risk for developing disease, tracking disease progression, and developing
therapeutics for patients with disease.
Three technologies the NIDDK believes are critical to accomplishing
these goals, and intends to actively pursue through the development
of Biotechnology Centers, are cDNA microarrays, oligonucleotide
chips, and Serial Analysis of Gene Expression, or SAGE. The development
of such advanced technologies requires the collaboration of investigators
with expertise in many fields, such as molecular biology, robotics,
bioinformatics, and statistics. As costs associated with these technologies
are high, the NIDDK proposes to support key aspects of infrastructure,
including the development and maintenance of appropriate databases
and special equipment.
Imaging technology has also advanced rapidly in recent years. New
imaging techniques, including relatively noninvasive techniques
such as magnetic resonance imaging (MRI), positron emission tomography
(PET), and absorption or fluorescence spectroscopy, represent a
revolution in research capabilities. It is now possible to image
small or deep structures that have until now been impossible. The
NIDDK has undertaken a number of initiatives to capitalize on these
technological advances.
The NIDDK has two initiatives designed to stimulate research on
the development of novel imaging methods to aid in the design of
clinical interventions. The first in is polycystic kidney disease
(PKD), a serious and costly disease. Although there have been important
advances in the molecular basis of PKD, clinical interventions to
slow destruction of kidney function are needed. Studies are beginning
to test whether imaging techniques can provide accurate and reproducible
markers of disease progression by monitoring changes in cyst size.
A second initiative on imaging focuses on the pancreatic beta cell.
It is designed to stimulate the development of techniques to the
ability to image, or otherwise noninvasively detect, beta cell mass,
function, and evidence of inflammation. It is anticipated that research
under this initiative will contribute to eventual development of
a clinical exam that could be used for monitoring disease progression
in response to therapy in diabetic patients and in individuals at
high risk for developing diabetes. Also, type 1 diabetes is now
being successfully treated using pancreas transplantation, and researchers
may soon be able to introduce healthy, functioning isolated pancreatic
islets into patients. In the course of developing this technique,
it would be of great clinical benefit to the patient to be able
to identify the location, number, viability, growth, and function
of these grafts and to be able to monitor their response to immune
modulating therapies. Because of the highly technical nature of
this work, collaboration between researchers in the fields of imaging,
beta cell biology, diabetology, chemistry, and engineering will
be necessary.
CLINICAL RESEARCH REPOSITORIES
The NIDDK is formulating an initiative to enhance clinical research
within the Institute by developing a resource repository system
that will be accessible to all of the NIH research community. The
NIDDK currently supports a variety of clinical trials that separately
collect and store enormous amounts of data, as well as patient samples
such as serum, tissue, urine, and DNA and RNA. Collecting and storing
such data and samples separately is expensive, often difficult to
monitor, and leads to duplication of efforts. The goal of this initiative
will be to create a common repository in which the many types of
data and specimens collected would be stored, monitored, and distributed
to the research community to facilitate future research studies.
A major strength of this resource repository will be the availability
of correlative clinical data, such as demographic, clinical, and
outcome data.
A network of cooperating institutions will be assembled by the
NIDDK and will work together to meet the goals of this initiative.
The NIDDK will also constitute a coordinating committee to govern
the repository as well to ensure smooth interactions among the cooperating
organizations. An outside scientific review group will be assembled
in consultation with the coordinating committee to review all requests
for use of the resources.
Operation of such a repository, including data management, would
also be subject to oversight by an Institutional Review Board. The
Board would review and approve a research protocol specifying the
conditions under which data and specimens may be accepted and shared,
thereby ensuring patient privacy and maintaining confidentiality
of data. This Board would also review and approve sample collection
protocols and informed consent documents for future distribution
of samples.
Human specimens are a resource to test hypotheses on normal biology
as well as on disease processes. Not only will utilization of human
specimens allow for the characterization of the molecular mechanisms
of disease, but it may clarify potential relationships between diseases
as well as complications associated with a particular disease. The
use of human specimens will also provide a unique resource for research
focused on developing new therapeutic interventions.
APPENDIX 1
Overview of Ongoing Scientific
Programs Supported by the NIDDK
What follows are detailed summaries of the major scientific programs
supported by each of the NIDDK's scientific operating divisions,
including the:
- Division of Diabetes, Endocrinology, and Metabolic Diseases
- Division of Digestive Diseases and Nutrition
- Division of Kidney, Urologic, and Hematologic Diseases
Division of Diabetes, Endocrinology,
and Metabolic Diseases
The Division of Diabetes, Endocrinology, and Metabolic Diseases
is responsible for extramural programs related to diabetes mellitus
and its complications; endocrinology and a variety of endocrine
disorders; and metabolism and metabolic diseases, including cystic
fibrosis.
Support for basic and clinical biomedical research, epidemiologic
and behavioral studies, and clinical trials is provided through
investigator-initiated research grants, program project and center
grants, cooperative agreements, contracts, and Small Business Innovative
Research awards.
The Division also supports a variety of career development and
training awards, as well as a limited number of resource, and research
and development contracts. In addition, the division provides leadership
in coordinating activities throughout the NIH and various other
Federal agencies.
Brief descriptions follow for each of the Division's major program
areas.
The Therapeutic Approaches to Diabetes Mellitus Program
encompasses studies of therapeutic approaches to achieving euglycemia.
Specific areas of support include: 1) studies on drug development;
2) transplantation of pancreas, or pancreatic endocrine cells (islets
or $-cells); 3) glucose sensors (including in combination with insulin
delivery systems to provide a closed-loop system); 4) cellular therapy
(including gene therapy approaches) that are being proposed to treat
or prevent either type 1 or type 2 diabetes; 5) studies in cell
culture to bioengineer or genetically manipulate cells with the
intent to produce an insulin-secreting cell or a glucose-responsive
insulin-secreting cell for the eventual treatment of diabetes; and
6) creation of animal models for therapeutic trials.
The Type 1 Diabetes Clinical Trials Program supports large,
multi-center clinical trials conducted under cooperative agreements
or contracts. The focus of the Diabetes Prevention Trial Type-1
(DPT-1) is to determine whether it is possible to prevent or delay
the onset of type 1 diabetes in individuals determined to be at
immunologic, genetic, and/or metabolic risk. The program also supports
the Epidemiology of Diabetes Interventions and Complications study,
an epidemiologic follow-up study of the subjects previously enrolled
in the Diabetes Control and Complications Trial.
The Type 2 Diabetes Clinical Trials Program supports large,
multi-center clinical trials conducted under cooperative agreements
or contracts. The Diabetes Prevention Program (DPP) is focused on
testing lifestyle and pharmacological intervention strategies in
individuals at genetic and metabolic risk for developing type 2
diabetes to prevent or delay the onset of this disease.
The Endocrine Pancreas Program focuses on studies on the
endocrine cells (alpha, beta, delta, etc.) of the pancreas and islets.
Specific areas of research include: 1) cell growth and development
or differentiation of these cells and identification of their growth/differentiation
factors; 2) identification of stem cells giving rise to endocrine
cells of the pancreas; 3) studies on regeneration, storage, preservation
and growth of pancreatic endocrine cells and islets; 4) studies
of islet structure; and 5) studies of the function and regulation
of these cells, including insulin and other hormone synthesis and
secretion.
The Insulin Receptor Program encompasses studies of cell
biology, structure, function and action of the insulin receptor.
Specific areas of support include: 1) molecular analysis of ligand
binding to receptor; 2) activation of the tyrosine kinase; 3) subsequent
insulin receptor function in signal transduction by serving as a
platform for the attachment of downstream signaling molecules involved
in insulin action; 4) the Insulin Receptor Signaling proteins (IRS)-1,2,3,4,
and other proteins containing Src Homology Domains (e.g., SH2).;
5) signaling cross-talk with other related and receptor signaling
pathways; and 6) regulation of gene expression.
The Insulin Resistance Program supports research on: 1)
the role of insulin resistance in the pathogenesis of type 2 diabetes
mellitus; 2) the relationship between insulin resistance and obesity;
3) the relationship between insulin resistance and physical inactivity;
4) new methods to measure peripheral insulin resistance; 5) the
molecular basis of decreased sensitivity to insulin; 6) insulin
receptor desensitization; 7) uncoupling of receptor activation to
downstream events; and 8) animal models of insulin resistance.
The Genetics of Diabetes Program endeavors to identify genes
that contribute to type1 and type 2 diabetes mellitus. Specific
areas of support include: 1) studies using animal models to identify
diabetes genes; 2) studies using quantitative statistical methods
to identify diabetes genes in human populations; and 3) development
of genetic resources, patient samples, and methods for studying
genetic linkage for diabetes.
The Complications Genetics Program is focused on elucidation
of the genes which increase an individual's susceptibility to the
complications of diabetes. This program supports research related
to the discovery of genes involved in the basic process/mechanisms
of complications. These mechanisms underlie the involvement of multiple
organs including the kidneys, nervous system, eye, and vasculature.
The Complications of Diabetes Program encompasses research
related to classical diabetic complications and the effect of diabetes
on any organ system. This includes, but is not limited to, the kidney,
eye, nervous system, vascular system, and reproductive system. Effects
include acute ketoacidosis, as well as the chronic complications
of diabetes. Research examines the molecular and cellular mechanisms
by which hyperglycemia mediates its adverse effects and the interrelationships
among the mechanisms potentially involved in the pathogenesis of
complications, including increased polyol pathway flux, alterations
of intracellular redox state, oxidative stress, glycation of structural
and functional proteins, altered expression of growth factors, enhanced
activity of protein kinase C, impaired synthesis of nitric oxide
and vasoactive prostacyclins, and altered metabolism of fatty acids.
The Hypoglycemia Program encompasses studies on the pathogenesis,
prevention, treatment and sequelae of hypoglycemia (low blood glucose)
in both type 1 and type 2 diabetes. Specific areas of research include:
1) studies to identify the biologic systems involved in recognition
and response to hypoglycemia; 2) studies designed to examine the
interplay of counter regulatory endocrine responses; and 3) studies
designed to ascertain the regulatory mechanisms for glucose homeostasis
and the cells involved in this regulation.
The Autoimmunity/Viral Etiology of Endocrine Disease Program
emphasizes support of investigator-initiated basic and clinical
research on the etiology and pathogenesis of type 1 diabetes and
autoimmune thyroid disease. Specific areas of support include: 1)
the autoimmune basis of the disease; 2) viral and other environmental
agents with potential roles in the etiology and pathogenesis of
disease; and 3) studies using animal models to further our understanding
of type 1 diabetes or autoimmune thyroid disease.
The Type 1 Diabetes Epidemiology Research Program focuses
on the distribution and determinants of type 1 diabetes and its
complications in populations, including community-based groups and
large patient populations. Specific areas of research include: 1)
epidemiologic studies on the genetic and environmental factors that
determine type 1 diabetes; 2) geographic and temporal variations
in the disease; 3) variations in disease frequency by race, socioeconomic
status, metabolic factors, and other determinants; 4) studies on
the etiology of diabetes, including identification of risk factors
that determine susceptibility to diabetes, and variations in the
distribution of risk factors within populations and within individuals;
5) research on the etiology and pathogenesis of diabetes complications
in well-defined populations; and 6) the genetic, lifestyle, and
environmental factors that predispose people with diabetes to complications.
Special emphasis is placed on epidemiologic studies of U.S. minority
populations in which the prevalence and severity of diabetes and
its complications is substantially elevated.
The Type 2 Diabetes Epidemiology Research Program focuses
on the distribution and determinants of type 2 diabetes, gestational
diabetes, and complications of diabetes in populations, including
community-based groups and large patient populations. Specific areas
of research include: 1) epidemiologic studies on the genetic and
environmental factors that determine type 2 diabetes; 2) geographic
and temporal variations in the disease; variations in disease frequency
by race, socioeconomic status, metabolic factors, and other determinants;
3) studies on the etiology of diabetes, including identification
of risk factors that determine susceptibility to diabetes, and variations
in the distribution of risk factors within populations and within
individuals; 4) research on the etiology and pathogenesis of diabetes
complications in well-defined populations; and 5) the genetic, lifestyle,
and environmental factors that predispose people with diabetes to
complications.
Special emphasis is placed on studies of U.S. minority populations
in which the prevalence and severity of type 2 diabetes and its
complications is substantially elevated.
The National Diabetes Data Group (NDDG) serves as the major
Federal focus for the collection, analysis, and dissemination of
data on diabetes and its complications. Drawing on the expertise
of the research, medical, and lay communities, the NDDG initiates
efforts to: 1) define the data needed to address the scientific
and public health issues in diabetes; 2) foster and coordinate the
collection of these data from multiple sources; 3) identify important
data sources on diabetes, and analyze and promulgate the results
of these analyses to the scientific and lay public; 4) promote the
timely availability of reliable data to scientific, medical, and
public organizations and individuals; 5) modify data reporting systems
to identify and categorize more appropriately the medical and socioeconomic
impact of diabetes; 6) promote the standardization of data collection
and terminology in clinical and epidemiologic research; and 7) stimulate
development of new investigator-initiated research programs in diabetes
epidemiology.
The Diabetes Mellitus Interagency Coordinating Committee (DMICC),
established in 1974 and chaired by the Director, Division of Diabetes,
Endocrinology and Metabolism, includes representatives from all
Federal departments and agencies whose programs involve health functions
and responsibilities relevant to diabetes mellitus and its complications.
Functions of the DMICC are: 1) coordinating research activities
of the NIH and those activities of other Federal programs that are
related to diabetes mellitus and its complications; 2) ensuring
the adequacy and soundness of these activities; and 3) providing
a forum for communication and exchange of information necessary
to maintain coordination of these activities.
The National Diabetes Education Program (NDEP), co-sponsored
by the NIDDK and the Centers for Disease Control and Prevention
(CDC), is focused on improving the treatment and outcomes for people
with diabetes, promoting early diagnosis, and ultimately preventing
the onset of diabetes. The goal of the program is to reduce the
morbidity and mortality associated with diabetes through public
awareness and education activities targeted to the general public,
people with diabetes and their families, health care providers,
and policy makers and payers. These activities are designed to:
1) increase public awareness that diabetes is a serious, common,
costly, and controllable disease that has recognizable symptoms
and risk factors; 2) encourage people with diabetes, their families,
and their social support systems to take diabetes seriously and
to improve practice of self-management behaviors; and 3) alert health
care providers to the seriousness of diabetes, effective strategies
for its control, and the importance of a team care approach to helping
patients manage the disease. Toward these ends, the NDEP is developing
partnerships with organizations concerned about diabetes and the
health care of its constituents.
The Diabetes Centers Program administers two types of center
awards, the Diabetes Endocrinology Research Centers (DERC) and the
Diabetes Research and Training Centers (DRTC). An existing base
of high quality diabetes-related research is a primary requirement
for establishment of either type of center. While not directly funding
major research projects, both types of center grants provide core
resources to integrate, coordinate, and foster the interdisciplinary
cooperation of a group of established investigators conducting research
in diabetes and related areas of endocrinology and metabolism. The
two types of centers differ in that the DERC focuses entirely on
biomedical research while the DRTC has an added component in training
and translation.
The Behavioral Research Program encompasses individual,
family, and community-based strategies aimed at prevention of diabetes
and its complications through lifestyle modifications, education,
and other behavioral interventions. Particular emphasis is placed
on development of culturally sensitive, lifestyle interventions
to prevent or treat diabetes in diverse high-risk populations, including
African-Americans, Hispanic Americans, and Native Americans. Specific
areas of research include: 1) the link between behavior and physical
health as it relates to diabetes and complications; 2) approaches
to improving health-related behaviors and to enhancing diabetes
self-management; and 3) other aspects of diabetes care.
The Regulation of Energy Balance and Body Composition Program
encompasses research on regulation of body composition by the hypothalamus
and circulating factors. Specific areas of support include: 1) endocrinology
of body composition, including interactions between nutrition, exercise,
and anabolic hormones; 2) neuropeptides and their receptors involved
in regulatory pathways controlling feeding behavior, satiety, and
energy expenditure; 3) interactions between hypothalamic-pituitary
adrenal axis and peripheral metabolic signals (for example, insulin,
leptin, glucocorticoids); 4) hormones and cytokines involved in
wasting syndromes (cancer, AIDS); 5) endocrine regulation of energy
balance via uncoupling proteins; and 6) hypothalamic integration
of peripheral endocrine and metabolic signals.
The Adipocyte Biology Research Program encompasses research
that addresses the development and physiology of the adipocyte cell.
Specific areas of support include: 1) studies on the properties
of transcription factors that regulate adipocyte differentiation;
2) research on the consequences of insulin action on adipocyte physiology;
and 3) use of animal and tissue culture models to understand adipocyte
biology.
The Glucose Transport Program seeks to develop a sound base
of fundamental science on all aspects of glucose transport in health
and disease, especially as it relates to glucose homeostasis in
diabetes and obesity. Specific areas of support include: 1) kinetics
and regulation of glucose uptake in muscle, liver, heart, gut, pancreas,
kidney, etc; 2) regulation and mechanism of glucose transporter
(GLUT) storage, translocation to the membrane, and gene expression
by insulin and other hormones, glucose, diet, exercise, and metabolic
state (fasting, obesity); 3) structure of glucose transporter; and
4) kinetic and structural studies of the transport proteins and/or
membrane channels of other nutrients, such as amino acids, ions
and metals.
The Glucose Metabolism Program emphasizes basic and clinical
studies of glucose and glycogen metabolism, which will lead to the
development of effective treatments for diabetes, glycogen storage
disease, obesity, burn injury, sepsis and trauma, and other metabolic
diseases. Specific areas of support include: 1) the measurement
of flux through pathways of glucose utilization, production, and
storage; 2) the mechanism of neural and hormonal regulation of glucose
homeostasis; 3) the effects of diet and exercise on glucose metabolism;
4) mathematical modeling of whole body or organ glucose metabolism;
5) interactions between carbohydrate, lipid, and amino acid metabolism
in health and disease; and 6) pancreatic hormone regulation of non-glycolytic
enzymes, especially those in the TCA cycle.
The Lipid Metabolism Program emphasizes basic and clinical
studies of the metabolism of fatty acid, triacylglycerols, cholesterol,
and related molecules, which will lead to the development of effective
treatments for diabetes, obesity, hypertriglyceridemia, hypercholesterolemia,
burn injury, sepsis, and other metabolic diseases. Specific areas
of support include: 1) flux and regulation of oxidation, storage,
and remodeling of dietary lipids in health and disease, and the
effects of diet and exercise; 2) regulation of lipid esterification,
hormone-sensitive lipases, and phospholipid metabolism; 3) membrane
transport and movement of lipids within the cell, or between organs
(binding proteins, carnitine transferases); 4) lipid-protein interactions;
5) metabolism of bioactive lipids and their precursors; and 6) lipid
peroxidation, especially associated with disease.
The Protein Metabolism Program encompasses basic and clinical
studies of protein, peptide, and amino acid metabolism, as well
as studies of purified protein structure, kinetics, function, and
enzyme reaction mechanism. Hormone regulation, effects of diet and
exercise, and the pathology associated with metabolic diseases are
of special interest. Specific areas of support include: 1) studies
of flux or regulation of total protein synthesis and turnover in
health and disease, including investigations of the specific enzymes
of protein and amino acid metabolism; 2) amino acid and peptide
membrane transport; 3) uptake, metabolism, and synthesis of specific
amino acids; 4) regulation of urea production and nitrogen balance;
5) role of cofactors, vitamins, and minerals in metabolism and enzyme
action; and 6) structure of specific classes of enzymes (redox,
phosphate transfer, etc.) elucidated by x-ray, NMR, or electron
microscopy.
The Steroid Metabolism Program emphasizes basic research
into the biochemistry, molecular biology, genetics, metabolism,
and biological function of steroids and similar molecules derived
from cholesterol, including sex steroids and other hormones (glucocorticoids,
mineralocorticoids), retinoids, cardiac glycosides, prostaglandins,
eicosanoids, and bile acids. Specific areas of support include:
1) the structure and reaction mechanisms of enzymes and enzyme-substrate
complexes in steroidogenesis and steroid interconversion pathways;
2) cholesterol activation for steroidogenesis, including cholesterol
esterase and intramitochondrial translocation of cholesterol; 3)
structure, function, and reaction mechanism of the p450 class of
enzymes; 4) estrogens and androgens in development; and 5) structure
and function of the mitochondrial cytochromes.
The Inborn Errors of Metabolism Program encompasses research
in the pathophysiology and treatment of genetic metabolic diseases.
Specific areas of support include: 1) studies of etiology, pathogenesis,
prevention, diagnosis, pathophysiology, and treatment of these diseases;
2) characterization of the genes, gene defects, and regulatory alterations
that are the underlying causes of these diseases; 3) studies of
the mutant enzyme and its effect on the structure and function of
the protein; 4) the development of animal models for genetic disease;
5) development and testing of dietary, pharmacologic, and enzyme
replacement therapies; and 6) development of stem cell transplantation,
both prenatally and postnatally, as a treatment for metabolic diseases.
The Cystic Fibrosis Research Program encompasses fundamental
and clinical studies of pathophysiology and development of new therapies.
Specific areas of support include: 1) the cystic fibrosis gene,
its protein product CFTR, and the molecular mechanisms by which
mutations cause disease; 2) roles of normal and mutant CFTR in transport
and other cellular processes; 3) genotype/phenotype studies; 4)
mechanisms underlying the lung inflammation and infection of cystic
fibrosis; 5) pancreatic insufficiency, malnutrition and growth failure,
impaired fertility, liver disease, and other complications of cystic
fibrosis; 6) development of new therapies by modulating or compensating
for the functional defects in mutant CFTR, stabilizing mutant CFTR,
and enhancing its targeting and integration into the cell membrane,
and safe and effective methods for gene therapy; 7) development
of animal or cell models; and 8) evaluation of therapeutic interventions
in cystic fibrosis in clinical studies or animal models.
The Gene Therapy Program encompasses research aimed at developing
basic and applied gene therapy for genetic metabolic diseases. Specific
areas of support include: 1) pilot and feasibility studies (R21)
to improve gene delivery systems; 2) studies of the basic science
of AAV, adenovirus, retrovirus, and lentivirus vectors; 3) studies
of non-viral methods of gene transfer such as liposomes or DNA-conjugates;
4) studies to target gene delivery to specific cell types; and 5)
gene therapy of stem cells to treat a genetic metabolic disease.
The Gene Therapy and Cystic Fibrosis Centers Program supports
three types of centers: Gene Therapy Centers (P30); Cystic Fibrosis
Research Center (P30); and Specialized Centers for Cystic Fibrosis
Research (P50). Gene Therapy Centers provide shared resources to
a group of investigators to facilitate development of gene therapy
techniques and to foster multidisciplinary collaboration in the
development of clinical trials for the treatment of cystic fibrosis
and other genetic metabolic diseases. Cystic Fibrosis Research Centers
(P30), and Specialized Centers for Cystic Fibrosis Research (P50)
provide resources and support research on many aspects of the pathogenesis
and treatment of cystic fibrosis.
The Bone and Mineral Research Program encompasses basic
and clinical research on the hormonal regulation of bone and mineral
metabolism in health and disease. Specific areas of support include:
1) endocrine aspects of disorders affecting bone, including osteoporosis,
Paget's disease, renal osteodystrophy, and hypercalcemia of malignancy;
2) pathogenesis, diagnosis and therapy of parathyroid disorders,
including primary or secondary hyperparathyroidism; 3) effects of
parathyroid hormone (PTH), parathyroid hormone related protein (PTHrP),
calcitonin, vitamin D, estrogen, retinoic acid, growth factors (e.g.
IGF-I, etc.), glucocorticoids, thyroid hormone, and other systemic
or local-acting hormones and their receptors on bone structure and
function; 4) bone active cytokines (e.g. TGF-beta, BMPs, CSF-1)
and their role(s) in bone cell biology; 5) studies of calcium homeostasis,
absorption, metabolism, and excretion, including the calcium activated
receptor (CaR); 6) basic and clinical studies of vitamin D; and
7) bone morphogenesis, including studies of signaling in the regulation
of developmental factors involved in bone formation (e.g. hedgehogs,
Hox genes).
The Thyroid Research Program is focused on normal thyroid
physiology and non-autoimmune thyroid disease, including thyroid
neoplasia. Specific areas of support include: 1) physiologic regulation
of the expression, processing, and secretion of thyroid hormones;
2) dysfunctional regulation of thyroid hormones that results in
disease; 3) studies of the etiology, pathogenesis, diagnosis, and
therapy of thyroid disorders; 4) studies on the deiodinase enzymes
that convert inactive thyroid hormone to active thyroid hormone;
and 5) studies on neural cells that are targets of regulation by
and feedback to the thyroid.
The Reproductive Endocrinology Program supports research
into the structure and function of gonadotropins, including, LH,
FSH, and hCG and their receptors. Specific areas of support include:
1) oligosaccharide modification and its effects on gonadotropin
function; 2) the metabolic responses of target tissue (e.g. prostate);
3) studies on the interaction of gonadotropins with their receptors;
4) the physiological effects of the hormones (e.g. menopause, age
of onset of menstruation); and 5) the development and study of analogs
of gonadotropins.
The Neuroendocrinology Program encompasses research on neuropeptides
of the hypothalamus. Specific areas of research support include:
1) physiological response to stress through the hypothalamic-pituitary-adrenal
axis; 2) neuropeptides and neuropeptide receptor signaling pathways;
3) gene regulation in the hypothalamus and pituitary gland; 4) diseases
of the pituitary, including neoplasia; 5) hypopituitary dwarfism;
6) identification and characterization of novel hypothalamic or
pituitary hormones; 7) tissue specific and developmental expression
of pituitary and hypothalamic genes; 8) pituitary hormone receptors
and actions on target tissues (e.g., GH IGF-1 axis); 9) neuropeptide
receptors in diagnosis and treatment of disease; and 10) neuroendocrine-immune
interactions.
The Growth Factor/Receptor Structure/Function Program encompasses
research on growth factors and cytokines, and their receptors, binding
proteins, and inhibitors. Specific areas of support include: 1)
regulation of expression of growth factors and their receptors in
endocrine cells and tissues; 2) structure/function studies; 3) role
of growth factors in endocrine tumor progression; 4) identification
of genes that are downstream targets of growth factor receptor activation;
5) modulation of growth factor action by binding proteins; and 6)
autocrine and paracrine actions of growth factors and cytokines
to regulate cell/tissue growth and function.
The Intracellular Signal Transduction Research Program encompasses
research aimed at understanding the structure and function of intracellular
signal transducing molecules. Specific areas of support include:
1) intracellular kinases, phosphatases, and anchoring proteins;
2) signaling mechanisms that have altered activity in response to
protein phosphorylation, Ca++ and cAMP; 3) approaches to solving
the three-dimensional structure of signaling proteins, including
crystallography and NMR; 4) functional analysis of these proteins,
including comparison of wild-type and naturally occurring or synthetic,
mutant proteins or expression of dominant-negative forms of the
proteins; 5) microscopic techniques to localize these proteins within
cells; 6) the identification of substrates for these signaling proteins;
and 7) the analysis of cross-talk among distinct signal transduction
pathways.
The G-Protein Coupled Receptors Program encompasses studies
on the G-protein coupled receptor superfamily. Specific areas of
support include: 1) cell surface, or seven transmembrane domain
(7-TM), receptors coupled to GTP-binding (G)-proteins for signal
transduction (e.g. beta-adrenergic receptor); 2) receptor structure
and function; 3) receptor down-regulation (homologous desensitization);
4) role(s) of mutated receptors in disease; and 5) coupling of signaling
through receptors to other membrane-bound effectors and or regulators,
such as adenylyl yclase, ion channels, protein phosphatases or kinases,
and other receptors. Signal transduction through GPCRs also includes
mechanisms of regulation of gene expression through nuclear proteins
such as the Cyclic Nucleotide Response Element Binding Protein (CREB)
and the CREB binding protein (CBP).
The Nuclear Hormone Gene Superfamily Program encompasses
basic and clinical research on members of the steroid hormone superfamily
(also known as the nuclear receptor superfamily). The program includes
structure/function studies and the role in signal transduction and
regulation of gene expression of the steroid hormones (glucocorticoids,
mineralocorticoids, progesterone, estrogens, androgens [testosterone],
DHEA) and the nuclear receptors, including thyroid hormone, vitamin
D, retinoids (RAR, RXR, vitamin A), PPARs, and orphan receptors
(LXR, SXR, Nur77, COUP-TF, and others). Topics covered include receptor
structure, interaction with cytoplasmic chaperones (e.g. Hsp90,
Hsp70, etc.), interaction with ligand, nuclear translocation, binding
to hormone response elements, interaction with nuclear accessory
proteins (e.g. SRC-1, N-CoR, CBP, histone acetylase/deacetylase,
GRIP1, etc.), as well as the basal transcriptional machinery, and
regulation of gene expression.
The Transcriptional Regulation of Metabolic Pathways Program
emphasizes research aimed at understanding the significance of gene
regulation to control of metabolism. Specific areas of support include:
1) the identification and characterization of transcription factors
and cis-acting regulatory elements in DNA using structural and functional
approaches; 2) identifying mechanisms whereby signal transduction
pathways elicit changes in gene expression; and 3) identifying the
molecular response to environmental cues, including hormonal stimulation,
nutrients, development, and stress.
The Protein Trafficking/Secretion/Processing Research Program
encompasses research aimed at understanding the mechanisms that
account for the fate of proteins after their initial translation.
Specific areas of support include: 1) protein folding; 2) post-translational
modifications and the enzymes that catalyze them; 3) the movement
of proteins in vesicles from the endoplasmic reticulum (ER) through
the golgi and endosomes and their ultimate secretion; 4) mechanisms
that account for vesicle formation (pinching-off) and vesicle fusion,
which are paramount to understanding trafficking; 5) the movement
of proteins in the direction opposite of secretion, including endocytosis
and retrograde transport; 6) proteins and small molecules that regulate
protein trafficking; and 7) proteasomes, ubiquitin conjugation,
and the N-end rule.
The Cytoarchitecture/Matrix Research Program encompasses
research into the properties and functions of intracellular and
extracellular, filamentous suprastructures that are involved in
hormone signaling, and endocrine and metabolic disorders. Specific
areas of support include: 1) the extracellular matrix with its constituent
collagens, hyaluronans, and proteoglycans; 2) studies of transmembrane
proteins that generate adherence through cell-matrix or cell-cell
interactions, including integrins, cadherins, selectins, and the
Ig superfamily; 3) intracellular structures formed by the actin
and intermediate filament networks; and 4) specialized structures
formed by these filaments, such as the contractile apparatus of
muscle cells.
The Hormone Distribution Program of the NIDDK makes available
to the research community human and animal pituitary hormones, antisera
to these hormones, and selected other hormonal and biological products.
Currently, approximately 180 research materials are distributed
through the National Hormone and Pituitary Program. Most of the
products are unavailable commercially. Approximately 7,000 individual
vials of human and animal hormones and antisera are awarded annually
to investigators for immunochemical research. Frozen human pituitaries
and rat hypothalami also are available for distribution to scientists
attempting to isolate or characterize novel hormones and peptides
or variants.
Division of Digestive Diseases
and Nutrition
The Division of Digestive Diseases and Nutrition is responsible
for managing programs in basic and clinical research, as well as
training and career development related to liver and biliary diseases;
pancreatic diseases; gastrointestinal disease, including neuroendocrinology,
motility, immunology, absorption, and transport in the gastrointestinal
tract; nutrient metabolism; obesity; eating disorders; and energy
regulation.
Brief descriptions follow for each of the Division's major program
areas:
The Liver and Biliary Program supports basic and clinical
research on both the normal function and the diseases of the liver
and biliary tract. Areas of basic research include: hepatic regeneration,
gene therapy, and liver cell injury, fibrosis, and apoptosis; basic
and applied studies on liver transplantation, including techniques
of preservation and storage; metabolism of bile acids and bilirubin;
physiology of bile formation; the control of cholesterol levels
in bile; and gallbladder and bile duct function. Areas of disease-oriented
research include: cholesterol and pigment gallstones; inborn errors
in bile acid metabolism; chronic hepatitis that evolves from autoimmune,
viral or alcoholic liver disease; and various liver ailments, such
as Wilson's disease, primary biliary cirrhosis, primary sclerosing
cholangitis, portal hypertension, hepatic encephalopathy, and Crigler-Najjar
syndrome.
The Pancreas Program encourages research into the structure,
function, and diseases (excluding cancer and cystic fibrosis) of
the exocrine pancreas. Areas of research interest include: hormonal
and neural regulation of electrolyte, fluid, and enzyme secretion;
receptors for secretagogues; stimulus-secretion coupling mechanisms;
gut-islet-acinar interrelations; organization and expression of
pancreatic genes; protein synthesis and export; tissue injury, repair,
and regeneration; physiology and pathology of trophic responses;
neural innervation; transcapillary solute and fluid exchange; duct
cell physiology and function; pancreas transplantation, storage,
and preservation; imaging of the pancreas; pancreatic insufficiency;
and acute and chronic pancreatitis and relevant experimental models.
The Gastrointestinal Transport and Absorption Program supports
research on the process of food digestion, and absorption and transport
in the gastrointestinal tract, including the synthesis and assembly
of digestive enzymes; the transport of water, ions, sugars, amino
acids, peptides, lipids, vitamins, and macromolecules; and the formation,
structure, and function of chylomicrons. Other areas of research
focus on the regulation of gene expression in the gastrointestinal
tract; the structure and function of the gut mucosa; the cytoskeletal
structure and contractility in brush borders; the growth and differentiation
of gastrointestinal cells in normal and disease states; intestinal
transplantation, storage, and preservation; and gastrointestinal
tissue injury, repair, and regeneration. Also supported are studies
on gastrointestinal diseases such as maldigestion and malabsorption
syndromes.
The Gastrointestinal Neuroendocrinology Program supports
basic and clinical studies on normal and abnormal function of both
the enteric nervous system and the elements within the central nervous
system that control the enteric nervous system. Neuroendocrine studies
supported include: histochemical and neurochemical analyses of the
enteric nervous system, electrical properties of enteric ganglia,
chemical neurotransmission, neural control of effector function,
and extrinsic nervous input. This program places a great deal of
emphasis on gastrointestinal hormones and peptides, including their
structure, biological actions, structure-activity relationships,
receptors, distribution, quantitation, metabolism, release, correlation
with physiological events, deficiency, and the role of time variation
in the data collected in the above studies. In addition, the program
supports studies on disease conditions associated with excessive
or inadequate secretion of neuropeptides.
The Gastrointestinal Motility Program focuses on the structure
of gastrointestinal muscles, the biochemistry of contractile processes
and mechanochemical energy conversion relations between metabolism
and contractility in smooth muscle, extrinsic control of digestive
tract motility, and the fluid mechanics of gastrointestinal flow.
Other studies and areas of interest include the actions of drugs
on gastrointestinal motility; intestinal obstruction; and diseases
such as irritable bowel syndrome (functional digestive disorders),
colonic diverticular disease, swallowing disorders, and gastroesophageal
reflux.
The Gastrointestinal Mucosa and Immunology Program focuses
on intestinal immunity and inflammation. Areas of interest include
ontogeny and differentiation of gut-associated lymphoid tissue;
migratory pathways of intestinal lymphoid cells; humoral antibody
responses; cell-mediated cytotoxic reactions and the role of cytotoxic
effector cells in chronic intestinal inflammation; genetic control
of the immune response at the mucosal surface; immune response to
enteric antigens in both intestinal and extra-intestinal sites;
granulomatous inflammation; lymphokines and cellular immune regulation;
leukotriene/prostaglandin effects on intestinal immune responses;
T-cell mediated intestinal cell injury; the intestinal mast cell
and its role in intestinal inflammation; approaches to optimal mucosal
immunoprophylaxis, including viral, bacterial, and parasitic diseases;
diseases such as gluten sensitive enteropathy, inflammatory bowel
disease, and gastritis; malabsorption syndromes; diarrhea; gastric
and duodenal ulcers; disease of the salivary glands (excluding cystic
fibrosis); the effects of prostaglandins and other treatment modalities
on the gastrointestinal tract; and the possible role of prostaglandins
or other agents in the pathogenesis and treatment of digestive diseases.
The Acquired Immunodeficiency Syndrome (AIDS) Program encourages
research into the characterization of intestinal injury, mechanisms
of maldigestion, and intestinal mucosal functions, as well as hepatic
and biliary dysfunction in patients with AIDS or in appropriate
animal models. In addition, studies are supported on the mechanisms
of nutrient malabsorption, deficiencies of various micronutrients,
nutritional management of the wasting syndrome, and other aspects
of malnutrition related to AIDS.
The Digestive Diseases Centers Program provides a mechanism
for funding shared resources (core facilities) that serve to integrate,
coordinate, and foster interdisciplinary cooperation between groups
of established investigators who conduct programs of high quality
research related to a common theme in digestive disease research.
An existing base of high quality digestive disease-related research
is a prerequisite for the establishment of a center.
The research emphases of centers in this program presently focus
on liver diseases, gastrointestinal motility, absorption and secretion
processes, inflammatory bowel disease, structure/function relationships
in the gastrointestinal tract, neuropeptides and gut hormones, and
gastrointestinal membrane receptors.
Nutritional Sciences Programs
The Nutrient Metabolism Program supports basic and clinical
studies related to the requirement, bioavailability, and metabolism
of nutrients and other dietary components at the organ, cellular,
and subcellular levels in normal and diseased states. Specific areas
of research interest include the understanding of the physiologic
function and mechanism of action/interaction of nutrients within
the body; the effects of environment, heredity, stress, drug use,
toxicants, and physical activity on problems of nutrient imbalance
and nutrient requirements in health and disease; and specific metabolic
considerations relating to alternative forms of nutrient delivery
and use, such as total parenteral nutrition. The program also supports
research to improve methods of assessing nutritional status in health
and disease.
The Obesity and Eating Disorders Program emphasizes research
on the biomedical and behavioral aspects of obesity, anorexia nervosa,
bulimia nervosa, and binge eating disorder. The goals of such research
are to establish a clear understanding of the etiology, prevention,
and treatment of these multifaceted conditions. Areas of research
interest focus on the physiological, metabolic, psychological, and
genetic factors that affect food choices, food intake, eating behavior,
appetite, and satiety; the effects of taste, smell, and gastric
and humoral (including neurotransmitter) responses in association
with dietary intake and subsequent behavior; the physiological and
metabolic consequences of weight loss or weight gain; the effect
of exercise on appetite and weight control; and individual variability
in energy utilization and thermogenesis. The program also encourages
investigations on the dietary determinants of the growth and control
of adipocyte size and number; the responsiveness of the adipocyte
to various metabolic and pharmacologic stimuli; the prevention of
obesity and other eating disorders; improved methods of assessing
body composition; examination of health risk factors associated
with specific degrees of obesity or body composition, and determining
the effect of exercise on body composition.
The Obesity Special Projects Program is a new program that
will support two major initiatives that began in Fiscal Year 1999.
First, is the Study of Health Outcomes of Weight-loss (SHOW) trial,
a major multi-center clinical trial that will examine the health
benefits and risks of sustained intentional weight loss in obese
diabetic patients. The cooperative agreement mechanism will be used
to develop the SHOW trial as a collaboration between the NIDDK and
the principal investigators selected through an RFA.
In addition, the NIDDK will be the lead Institute for developing
a trans-NIH initiative on obesity prevention. This will include
support for pilot studies of innovative approaches to prevent obesity
in high-risk populations (ranging from children through the elderly).
Various mechanisms will likely be used to permit a number of institutes
to fund small grants in obesity prevention. This initiative is being
coordinated trans-NIH through the NIH Division of Nutrition Research
Coordination. The NIDDK grants arising from this initiative will
be administered through the Obesity Special Projects Program.
Clinical Nutrition Research Units (CNRUs) comprise the Clinical
Nutrition Research Units Program. A CNRU integrates the array
of research, educational, and service activities focussed on human
nutrition in health and disease. It serves as the focal point for
an interdisciplinary approach to clinical nutrition research and
for the stimulation of research in areas such as improved nutritional
support of acutely and chronically ill persons, assessment of nutritional
status, effects of disease states on nutrient needs, and effects
of changes in nutritional status on disease.
The Obesity/Nutrition Research Centers (ONRC) Program encourages
a multidisciplinary approach to obesity and nutrition research.
The goal of an ONRC is to help coordinate and strengthen support
for research activities primarily by providing funds for core facilities
and associated staff that serve the various projects of the ONRC
on a shared basis. This approach has ensured that an ONRC has multiple
sponsors, both federal and non-federal, and thereby reduces the
likelihood that the ONRC will become unduly dependent on any one
source of funds for its continued operation. The specific objectives
of an ONRC include efforts to create or strengthen a focus in biomedical
research institutions for multidisciplinary research in obesity
and nutrition; to develop new knowledge concerning the development,
treatment, and prevention of obesity and eating disorders; to understand
control and modulation of energy metabolism; to understand and treat
disorders associated with abnormalities of energy balance and weight
management, such as in anorexia nervosa, AIDS, and cancer; and to
strengthen training environments to improve the education of medical
students, house staff, practicing physicians, and allied health
personnel with regard to these conditions.
The Clinical Trials Program supports clinical trials on
Helicobacter pylori; primary biliary cirrhosis; adult and
adolescent obesity; inflammatory bowel disease; irritable bowel
syndrome; primary sclerosing cholangitis; pancreatitis; nonulcer
dyspepsia; prevention, management, and treatment of portal hypertension;
recurrent liver disease after transplantation; and hepatitis B and
C.
The Epidemiology and Data Systems Program serves as the
major Federal focus for the collection, analysis, and dissemination
of data on digestive diseases and their complications. The Epidemiology
component includes studies that address risk factors for disease
occurrence and disease prognosis or natural history. The Data Systems
component includes databases and biological repositories that support
clinical and epidemiologic studies. A database is a systematic,
usually prospective, collection of clinically important information
that is stored and retrieved in electronic format. Biological repositories
may include genetic, serum, and tissue banks. Both the epidemiology
and data systems components relate solely to human studies.
The Research Training and Career Development Program offers
research training and career development opportunities in support
of the programs of the Division of Digestive Diseases and Nutrition.
Four types of National Research Service Awards and one Research
Career Development Award are available.
Division of Kidney, Urologic,
and Hematologic Diseases
The Division of Kidney, Urologic, and Hematologic Diseases is responsible
for oversight and planning of investigative programs designed to
address some of the nation's major chronic health problems. Diseases
of the kidney and urologic systems and hematologic disorders include
conditions that shorten life expectancy for millions of Americans,
and produce huge health care costs and substantial disability. The
challenge faced by the Division is to insure that the health problems
within its scope attract rigorous and innovative investigation,
and benefit from the current climate of enhanced scientific opportunity.
It is clear to all observers of the biomedical research arena that
we are in the midst of an era of accelerating scientific insights
into biological disease processes. To a substantial extent this
excitement is enhanced by the anticipation of enormous new insights
emerging from a complete catalog of all human genes emerging from
the Human Genome Project. But with this excitement comes a growing
expectation that in the coming decade this knowledge will yield
substantial direct health benefits. This climate of expectation--the
responsibility to insure that the promise of new knowledge is realized--gives
particular urgency to research planning and oversight processes
at both the Institute and Divisional level.
Brief descriptions follow for each of the Division's major program
areas:
The Renal Diseases Program supports basic, applied, and
clinical research relating to the physiology and pathophysiology
of the kidney; structural and functional effects of various hormones
and pharmacological agents on metabolism, filtration, transport,
and fluid electrolyte dynamics of the kidney; and the effects of
drugs and nephrotoxins on the kidney. Other areas of research supported
by the program include fundamental and applied research addressing
the different forms of glomerulonephritis, the immune and non-immune
mechanisms of glomerular injury, tubulointerstitial nephritis, as
well as vascular diseases.
The Renal Diseases Program is composed of several specific
kidney programs:
The Renal Physiology and Cell Biology Program primarily
focuses on the normal development, structure, and function of the
kidney, including its biochemistry, metabolism, transport, and fluid
electrolyte dynamics. Research is supported on the cellular and
subcellular molecular mechanisms involved in transport processes
that regulate solute and water excretion, with emphasis on how abnormalities
in these transport processes and enzymes may contribute to disease
states such as renal stones, hypertension, acid-base abnormalities,
and progression of renal disease. Of special interest are studies
to elucidate factors that contribute to acute renal failure, which
will lead to its prevention or make the disease less severe and,
ultimately, speed recovery of kidney function. This program emphasizes
applying cellular and molecular biologic techniques to identifying
and characterizing growth factors and signal transduction systems
and transport systems and respective genes, and to elucidating the
structure of genes and their regulation during kidney organogenesis,
which may continue to operate in the mature kidney.
The Chronic Renal Diseases Program supports basic and clinical
research on renal development and disease, including: 1) causes,
pathogenetic mechanisms, and pathophysiology; 2) morphological and
functional markers and diagnostic measures; 3) underlying mechanisms
leading to progression of renal disease; 4) functional adaptation
to progressive nephron loss; 5) natural history of progressive renal
diseases; and 6) identification and testing of possible therapeutic
interventions to prevent development or halt progression of renal
disease.
Research in this program includes the primary glomerulopathies
and renal disease from systemic diseases that collectively account
for more than 50 percent of all cases of treated end-stage renal
disease. Of special interest are studies of inherited diseases such
as polycystic kidney disease; congenital kidney disorders; and immune-related
glomerular diseases, including IgA nephropathy and the hemolytic
uremic syndrome.
The End-Stage Renal Disease Program promotes research to
reduce morbidity and mortality from bone, blood, nervous system,
metabolic, gastrointestinal, cardiovascular, and endocrine abnormalities
in end-stage kidney failure, and to improve the effectiveness of
dialysis and transplantation. Of special interest is research on
hemodialysis membrane reuse and alternative dialyzer sterilization
methods; more efficient, biocompatible membranes; high-flux hemodialysis;
and criteria for adequacy of dialysis. We are also interested in
research on adequacy, appropriate dialysis dose, and infectious
complications in peritoneal dialysis, as well as criteria to identify
patients best suited for this therapy. The program seeks to increase
graft and patient survival and organ availability through research
to improve organ preservation, transplantation across ABO blood
groups, HLA cross-matching of donors with recipients, immunosuppression,
infection control, and organ donations, especially by African American
and other minority groups. Of special interest is research on the
causes and prevention of progressive loss of renal function in long-term
renal transplants.
The Diabetic Nephropathy Program supports basic research
on the pathophysiology and pathogenesis of diabetic nephropathy,
natural history studies, and clinical trials through the investigator-initiated
R01 mechanism. Fundamental research focuses on the molecular pathogenesis
of extracellular matrix expansion and glomerulosclerosis, the role
of the renin-angiotension system and growth factors, and the identification
of treatments to prevent renal scarring. Of special interest are
studies to understand the mechanisms of progressive renal scarring,
to identify genes that either protect people from or predispose
them to diabetic nephropathy, and to identify early markers of increased
risk of the disease.
The Pediatric Nephrology Program supports basic and clinical
research directed towards the study of renal diseases that affect
children. The majority of diseases leading to end-stage renal failure
have their onset in childhood. The program includes research focusing
on normal and disordered renal developmental processes, pathogenetic
mechanisms and pathophysiology of acute and chronic renal diseases,
morphologic and functional markers of renal disease, underlying
mechanisms leading to progressive renal disease, functional adaptation
to nephron loss, natural history of progressive renal diseases,
identification of therapeutic interventions to prevent or slow progression
of renal diseases, and testing of these interventions through clinical
trials. Areas of particular interest are: 1) inherited and congenital
renal diseases such as renal dysplasia, congenital nephrotic syndrome,
Alport syndrome, and polycystic kidney disease; 2) molecular, genetic,
and cellular aspects of normal and abnormal renal development; 3)
primary glomerular disease; 4) renal involvement in systemic disease;
5) diabetic nephropathy; 6) renal artery disease and hypertensive
renal disease; 7) renal disease progression; and 8) chronic renal
insufficiency, pathophysiology, management, complications, and dialysis
and transplantation in the pediatric population.
The Renal Diseases Epidemiology Program supports descriptive
and analytic epidemiologic research, including development and analysis
of surveillance databases, cross-sectional surveys, prospective
observational studies, and case-control studies (for evaluating
rare diseases). Key areas of interest include preventing disease;
developing early markers of injury; defining risk factors for morbidity
and mortality; and increasing evaluation of kidney disease measurements
and outcomes in ongoing observational studies. The program is dedicated
to increasing the availability of epidemiologic data through both
development of new databases and full utilization of existing Federal,
state, and private sources of data. The United States Renal Data
System (USRDS) is funded under a contract through the Renal
Diseases Epidemiology Program of the NIDDK. Mechanisms are currently
being developed to enhance the availability of USRDS data to the
biomedical and health services research community. In addition,
the program is working with the National Center for Health Statistics
to develop and analyze the nephrology component measured in the
third National Health and Nutrition Examination Survey.
The Urology Program supports basic, applied, and clinical
research in prostate and prostate diseases; diseases and disorders
of the bladder; male sexual dysfunction; urinary tract infections;
urinary tract stone disease; and pediatric urology, including developmental
biology of the urinary tract. The Program supports projects on the
normal and abnormal function of the genitourinary tract, molecular
genetic and molecular biological approaches to the mechanisms of
normal and abnormal development and growth of the genitourinary
tract, regulation and function of the cells, tissues, and organs
of the genitourinary tract; pathophysiology of urological disorders
and diseases; and, clinical investigations of urological disorders
and therapeutic interventions in these disorders.
A research priority in the Urology Program is the study of chronic
inflammatory disorders of the lower urinary tract. The program encourages
studies from diverse clinical and basic science disciplines for
the investigations of these disorders. Realizing that knowledge
about the etiology, pathophysiology, treatment, and epidemiology
of these disorders is still limited, an innovative and multidisciplinary
approach to investigation is encouraged.
A unique aspect of the Urology Program in the area of prostatic
growth and development is the cooperative funding with the National
Cancer Institute of prostate research which focus on normal and
malignant prostate growth.
The Pediatric Urology Program encourages and supports basic
and clinical studies, including: 1) bladder development; 2) urinary
tract development; 3) prenatal intervention for urinary tract disorders;
4) vesicoureteral reflux; 5) enuresis; 6) urinary tract and bladder
outlet obstruction; 7) congenital abnormalities such as posterior
urethral valves and bladder exstrophy; and 8) bladder abnormalities
associated with spina bifida.
The Urologic Diseases Epidemiology Program supports descriptive
and analytic epidemiology, including development and analysis of
surveillance databases, cross-sectional surveys, prospective observational
studies, and case-control studies (for evaluating rare diseases).
Key areas of interest include preventing disease, developing early
markers of injury, defining risk factors for morbidity and mortality,
and increasing evaluation of urologic disease measurements and outcomes
in ongoing observational studies. The program is dedicated to increasing
the availability of epidemiologic data through both development
of new databases and full utilization of existing Federal, state,
and private sources of data. The program is working with the National
Center for Health Statistics to develop and analyze the urology
component measured in the third National Health and Nutrition Examination
Survey.
The Hematology Program emphasizes a broad approach to understanding
the normal and pathologic function of blood cells and the blood
forming (hematopoietic) system. Major areas of interest include
diseases such as sickle cell anemia, thalassemias, aplastic anemia,
iron deficiency anemia, hemolytic anemias, and thrombocytopenia.
Other areas of interest include l) morphologic, physiologic, and
biochemical aspects of the formation, mobilization, and release
of blood cells; 2) erythrocyte metabolism and physiology, globin
synthesis, ion transport, and enzymatic pathways; 3) iron metabolism
and absorption; 4) erythropoietin and other hematopoietic growth
factors; 5) hemoglobin metabolism, structure, function, and genetic
control; 6) porphyrins and porphyrias; 7) metabolism and function
of white blood cells; and 8) development of genetic therapies.
The Hematology Program has issued several recent initiatives to
emphasize research on the biology and genetic regulation of stem
cells. Stem cells are crucial to the eventual accomplishment of
gene therapy and for improved transplantation of bone marrow cells.
An additional area of long-term priority has been the development
of improved iron chelating drugs to reduce the toxic iron burden
in people who receive multiple blood transfusions for diseases such
as Cooley's anemia (thalassemia major).
The Hematology Program is leading a major trans-NIH initiative
to make zebrafish genomic resources available to the research community.
As a vertebrate, the zebrafish, Danio rerio, is more closely
related to humans than are yeast, worms or flies. The zebrafish
has a number of valuable features that make it a highly desirable
model for the study of vertebrate development. Some genomic resources
already exist to facilitate identification of the molecular defects
that underlie mutations already known in the zebrafish. The utility
of these resources is limited, however, and the mapping infrastructure
is insufficiently developed to fully exploit the power of the genetics
of this organism. The NIDDK and the National Institute of Child
Health and Human Development co-chair the newly established, NIH-wide
Zebrafish Coordinating Committee, which manages genomics projects
and further develops the utility of the model.
Division-Wide Programs include:
The Centers Program, which consists of: 1) George M. O'Brien
Kidney and Urologic Research Centers; 2) Research Centers of Excellence
in Pediatric Nephrology and Urology; and 3) Centers of Excellence
in Molecular Hematology. The goal of the Centers Program is to reduce
adult and pediatric mortality and morbidity from kidney, urologic,
and hematologic diseases. The program provides a focus and means
for clinical and basic science disciplines to improve the diagnosis,
treatment, and prevention of these conditions.
The George M. O'Brien Kidney and Urologic Research Centers conduct
interdisciplinary investigations that address basic, clinical, and
applied aspects of biomedical research in renal and genitourinary
physiology and pathophysiology. Kidney diseases of hypertension
and diabetes, renal and urinary tract dysfunction in obstructive
diseases of these organs, immune and nonimmune-related mechanisms
of glomerular injury and kidney disease, nephrotoxins and cell injury,
and benign prostatic hyperplasia are emphasized.
The Research Centers of Excellence in Pediatric Nephrology and
Urology currently conduct coordinated, interdisciplinary and multi-institutional
studies on mechanisms regulating the development of the kidney and
urinary tract and on childhood nephrotic syndrome.
The Centers of Excellence in Molecular Hematology have integrated
teams of investigators from a wide range of specialties; share specialized,
often expensive equipment and staff; and serve as regional or national
resources for other researchers. The Centers provide a focus for
multi-disciplinary investigations into gene structure and function;
the cellular and molecular mechanisms involved in the generation,
maturation and function of blood cells; and the development of strategies
for the correction of inherited diseases.
The Clinical Trials Program works in concert with other
programs of the Division to develop and manage cooperative clinical
trials to prevent or retard major chronic kidney, urologic, and
hematologic diseases. The program coordinates and monitors patient
recruitment and adherence to interventions for: 1) the Hemodialysis
Study; 2) the African American Study of Kidney Disease and Hypertension;
3) the Interstitial Cystitis Clinical Trials Group; 4) the Medical
Therapy of Prostatic Symptoms; and 5) the Chronic Prostatitis Collaborative
Research Network.
The Developmental Biology and Non-mammalian Systems Program
supports fundamental investigation likely to enrich our basic investigative
programs. Two broad topic areas, developmental biology and non-mammalian
systems, continue to be of substantial relevance to this goal. The
Division's basic programs in all three subject areas--Kidney, Urology
and Hematology--have experienced increases in grants awarded in
developmental biology, a trend we hope to see continued. The Division
has identified several barriers to the full exploitation of the
rich potential of non-mammalian systems, including their unfamiliarity
to study sections and the difficulties of identifying appropriate
collaborations. Building bridges between the communities traditionally
supported by our programs and experts in other relevant model systems
will continue to be one focus of the Division's workshop planning.
A workshop on use of Non-Mammalian model systems for study of epithelial
transport is planned for December 1999.
The Division has assumed a leadership position in trans-NIH planning
for the Zebrafish Program. The zebrafish is a model organism
that has emerged as a very valued scientific tool to understand
vertebrate development. A major strength of this zebrafish system
is the feasibility of mutagenesis screens and positional cloning
to identify developmentally important genes. In the coming fiscal
year two goals are proposed for this program: 1) establishment of
a physical map of the zebrafish genome; and 2) funding of mutagenesis
and phenotyping projects to identify additional genetic defects.
Funding of these projects will occur through collaborative efforts
of the trans-NIH zebrafish coordinating committee, with participation
from 18 institutes.
The Genomic Resources for Kidney and Urology Program addresses
one of the most promising of the new scientific approaches emerging
from the human genome project, namely, the use of systematic methods
to assess changes in gene expression in response to injury or disease.
A prerequisite for application of these methods to kidney and urology
disease is the availability of organ-specific gene profiles. The
Division is actively engaged in exploring the best ways to facilitate
availability of these methods to our investigative communities.
The Human Immunodeficiency Virus (HIV) Program supports
basic and clinical studies on renal and genitourinary tract structure
and function, and hematopoietic function in individuals with HIV
infection. The program's interests include: 1) the pathogenetic
mechanisms of the viral infection on the kidney and genitourinary
tract; 2) site(s) of viral replication and/or spread, and the resulting
organ dysfunction; and 3) hematologic abnormalities associated with
HIV infection and its effects on stem cells and marrow function.
Studies on HIV infection focus on: 1) the effect of HIV therapies
on marrow function and clinical course of dialysis and transplant
patients; 2) the potential interactions of HIV infection and therapies
on the immunosuppressive therapy used to prevent transplant rejection;
and 3) the effect on organ function. An important new emphasis is
research into the development of strategies for gene therapy for
HIV, using modification of hematopoietic stem cells. This is based
on recent reports of protection against HIV through the use of human
fetal stem cells transduced with retroviral vectors expressing a
ribozymal gene.
The Manpower Program offers research training and career
development awards in the clinical and basic sciences for predoctoral
and postdoctoral training and career development. Of particular
program interest is training and development of under-represented
minority investigators for retention in academic research and the
training of more researchers in epidemiology, health services research,
pediatric urology and nephrology, pathology, and materials science.
The Minority Health Program supports research on diseases
that disproportionately affect minority populations. The program
is especially interested in research on the pathogenetic mechanisms,
risk factors, and potential treatments for renal disease and hypertension,
kidney disease of diabetes, and hemoglobinopathies such as sickle
cell disease.
The Small Business Innovation Research (SBIR) Program promotes
technological innovation within the American small business community
by giving small businesses an increased role in Federal biomedical
research. The program works to attract private capital to commercialize
the results of federally funded research into basic mechanisms of
organ and tissue function and diseases of the kidney, urologic,
and hematopoietic systems. The Division's SBIR Program encourages
research aimed at understanding the physiology and pathophysiology
of diseases of the kidney, urinary tract, and blood and blood-forming
systems. The Program promotes the development of: 1) cellular and
molecular biology technologies to enhance research in these diseases;
2) bacterial-resistant biomaterials for urinary catheters; 3) noninvasive
methods for measuring renal function; 4) tissue engineering; 5)
animal models; 6) data and cell banks of large families with polycystic
or diabetic kidney diseases; 7) improved methodology for purifying
and isolating hematopoietic stem cells; 8) methods to isolate, purify,
and characterize cellular receptors for hematopoietic growth factors;
9) development of noninvasive means to measure body iron; 10) generation
of cDNA libraries from hematopoietic lineages; and 11) population
studies to identify prevalence, incidence, demographics, risk factors,
etc., for kidney and urologic diseases.
The Small Business Technology Transfer Research (STTR) Program
is authorized under the same law as the SBIR Program. While both
programs have similar goals, the STTR Program also encourages and
requires collaboration and technology transfer between small businesses
and research institutions. The Division's STTR program is interested
in supporting research on tissue modeling techniques for renal and
urinary tract diseases and basic hematological processes.
The Kidney, Urologic, and Hematologic Diseases Interagency Coordinating
Committee was established to coordinate research in kidney,
urologic, and hematologic diseases and to aid the efficient exchange
of information among NIH institutes and other Federal agencies.
The committee meets regularly and prepares an annual report.
The National Kidney and Urologic Diseases Information Clearinghouse
was established in 1987 in response to the Health Research Extension
Act of 1985. Its goal is to increase knowledge about kidney and
urologic diseases among patients, health professionals, and the
public. The clearinghouse collects, screens, and disseminates information
and educational materials about kidney and urologic diseases. The
Clearinghouse also works closely with local and national organizations,
as well as professional groups interested in these diseases for
the purpose of developing and exchanging educational materials.
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