EVOLUTIONARY MECHANISMS IN INFECTIOUS DISEASES

Release Date:  August 18, 1999

PA NUMBER:  PA-99-147

National Institute of General Medical Sciences
National Institute of Dental and Craniofacial Research

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES
DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED
WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

The goal of the program announcement is to encourage development of a
predictive science of infectious diseases by applying the perspectives,
theories, and methods from evolutionary biology to important issues of disease
emergence, prevention and the consequences of treatment.  Research projects
involving interdisciplinary collaborations are an explicit goal of this
program announcement.  Approaches might include, but are not limited to,
microbiology, population dynamics, chemistry, biochemistry, and computational
biology. The focus is limited to discovery of fundamental biological
principles rather than on detailed knowledge or treatment of specific
diseases.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This PA, Evolutionary Mechanisms in
Infectious Diseases, is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2000" at
http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, for-profit and non-
profit organizations, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local governments, and eligible
agencies of the Federal Government.  Foreign institutions are not eligible for
program project (P01) grants.  Racial/ethnic minority individuals, women, and
persons with disabilities are encouraged to apply as principal investigators.

MECHANISM OF SUPPORT

This PA will use the National Institutes of Health (NIH) research project
grant (R01) and program project grant (P01) mechanisms.  Supplements to
existing NIH grants will also be considered.  Responsibility for the planning,
direction, and execution of the proposed project will be solely that of the
applicant.  The total project period for an application submitted in response
to this PA may not exceed five years.

For R01 grants in requesting less than $250,000 in direct costs per year,
specific application instructions have been modified to reflect "MODULAR
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.
Complete and  detailed instructions and information on Modular Grant
applications can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm

RESEARCH OBJECTIVES

Background

A predictive science of infectious disease depends on our ability to
anticipate with some confidence the behavior of host/parasite systems. 
Predictions might include when and where new infectious diseases will emerge,
under what conditions drug resistance will arise, the consequences of
therapeutic interventions, and the impact of ecological changes.

Infectious systems consisting of parasite(s), vector(s), and host(s) are
subject to dynamic interactions at many levels.  For example, the ability of
an infectious species to colonize plant or animal hosts, to proliferate, to
cause disease, and to spread depends on a variety of factors, such as its
genetic characteristics, its life history, and its mode of transmission, all
of which are subject to evolutionary change. The ability of a host species to
prevent, control, and/or promote interactions similarly depends on its innate
defense system (including immune defenses), its behavior, its environment, and
human intervention.  Population dynamics, including population density,
migration, population subdivision, and competition for resources, affect the
evolution of pathogens, vectors and hosts.

Evolutionary biology, molecular biology, genetics, systematics, chemistry,
biochemistry, mathematics, and other disciplines, will contribute
significantly to the development of a predictive science of infectious
systems.  For example, identifying the origins and host ranges of infectious
agents requires a variety of molecular, genetic, mathematical, and
evolutionary tools.  Intervention to prevent or treat infections by behavior
modification, control of vectors, vaccination, drug therapy or other means
influences a variety of dynamic evolutionary processes in individual hosts,
communities of hosts, and communities of pathogenic organisms.  Understanding
the conditions under which interventions fail (e.g., antibiotic resistance or
reversion of live vaccines to virulence) and designing protocols to prevent
these failures requires application of evolutionary understanding and the
complexity of chemical interactions.  Multidisciplinary approaches are
essential for anticipating the conditions under which new infectious diseases
will emerge and old ones will re-emerge.

Although there is widespread interest in understanding, preventing, and
treating infectious diseases and anticipating their emergence and re-
emergence, research into evolutionary aspects of infectious systems has been
limited.  With a few exceptions, broadly interdisciplinary approaches are
rarely employed in infectious disease research or in the design of protocols
to prevent and treat infections.  The goal of this initiative is to remedy
this situation by supporting collaborations among scientists with diverse
areas of expertise.

Scientific Objectives

Applications for research projects responsive to this program announcement
should address broad evolutionary questions that are relevant to infectious
diseases in general. Because host/parasite and other symbiotic systems exhibit
a continuum of behavior, ranging from beneficial to pathological associations,
general evolutionary principles can be expected to emerge from studies using a
variety of models.  For example, plant and microbial systems will be
considered when they are used to address fundamental mechanisms of evolution. 
Human studies are included when the goal of the research is basic knowledge of
the evolution of infectious systems rather than a specific disease entity. 
Studies that combine quantitative, theoretical, and experimental approaches
are especially encouraged.  Applicants must clearly explain how the proposed
approaches and perspectives are expected to contribute to development of a
predictive science of infectious diseases.

Within the areas of investigation described below, relevant applications could
focus on, but are not limited to, one or more of the following aspects:

1.  Causes and sources of infectious diseases.
o  Genetic variation and structure of pathogen populations and the genetic
relationships between commensal and pathogenic members of closely related taxa
o  Population analyses of the contributions and sources of the vertical and
horizontal transfer of genes and accessory elements coding for virulence
determinants, host range and specificity, and drug resistance
o  Genetic factors (pathogen, host or vector) responsible for geographic and
temporal variation in disease frequency and severity

2.  Interactions between hosts and pathogens.
o  Contribution of population dynamic and evolutionary processes to the
pathogenesis and virulence of infecting organisms
o  Establishment of model systems to explore the relationship between the
evolution of pathogenic organisms and factors affecting host susceptibility,
including ecological, social and other environmental factors
o  Mechanisms of chemical signaling and communication

3.  Consequences of intervention strategies.
o  Within-host population dynamics related to intervention strategies,
including reversion to virulence of live vaccines (as opposed to outgrowth of
existing unattenuated organisms), as well as evolution of resistance following
antimicrobial drug therapy or vaccination
o  Establishment of model systems (either in vitro systems, or in vivo systems
involving non-human pathogens and/or animal, microbe, or plant hosts) to
predict the ecological and evolutionary consequences of programs involving
host behavior, vaccination, antimicrobial drug therapy, and other intervention
strategies on pathogen, host, and vector populations
o  Novel mechanisms of antibiotic action
o  Use of evolutionary approaches to create new strategies for drug
development and delivery
o  Identification of new resistance mechanisms, including how they arose

4.  Establishment of model systems to explore the environmental, physiological
and genetic factors responsible for generating and maintaining variation in
pathogen, vector, and host populations, including co-evolutionary dynamics.

5.  Natural history of pathogenic organisms.
o  Evolutionary basis for the normal range of pathogen habitats and hosts
o  Establishment of model systems to explore the molecular basis of host
barriers that must be overcome by pathogens in order to extend their ranges
o  Establishment of model systems to explore the molecular, individual, and
population dynamics of extending the niche or host range of a pathogen.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of the NIH that women and members of minority groups and
their subpopulations must be included in all NIH supported biomedical and
behavioral research projects involving human subjects, unless a clear and
compelling rationale and justification is provided that inclusion is
inappropriate with respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of 1993
(Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects should read the
"NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical
Research," which have been published in the Federal Register of March 28, 1994
(FR 59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23,
Number 11, March 18, 1994 available on the web at the following URL address:
http://grants.nih.gov/grants/guide/notice-files/not94-100.html

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of NIH that children (i.e., individuals under the age of 21)
must be included in all human subjects research conducted or supported by the
NIH, unless there are scientific and ethical reasons not to include them. 
This policy applies to all initial (Type 1) applications submitted for receipt
dates after October 1, 1998.

All investigators proposing research involving human subjects should read the
"NIH Policy and Guidelines on the Inclusion of Children as Participants in
Research Involving Human Subjectsþ that was published in the NIH Guide for
Grants and Contracts, March 6, 1998, and is available at the following URL
address: http://grants.nih.gov/grants/guide/notice-files/not98-024.html

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) and will be accepted at the standard application deadlines as indicated
in the application kit.  Application kits are available at most institutional
offices of sponsored research and may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/435-
0714, email: GrantsInfo@nih.gov.

Applicants planning to submit an investigator-initiated new (type 1),
competing continuation (type 2), competing supplement, or any amended/revised
version of the preceding grant application types requesting $500,000 or more
in direct costs for any year are advised that he or she must contact the
Institute or Center (IC) program staff before submitting the application, i.e,
as plans for the study are being developed. Furthermore, the application must
obtain agreement from the IC staff that the IC will accept the application for
consideration for award. Finally, the applicant must identify, in a cover
letter sent with the application, the staff member and Institute or Center who
agreed to accept assignment of the application.

This policy requires an applicant to obtain agreement for acceptance of both
any such application and any such subsequent amendment. Refer to the NIH Guide
for Grants and Contracts, March 20, 1998 at
http://grants.nih.gov/grants/guide/notice-files/not98-030.html

MODULAR GRANT INSTRUCTIONS FOR R01 GRANTS REQUESTING LESS THAN $250,000 DIRECT
COSTS PER YEAR.

The modular grant concept establishes specific modules in which direct costs
may be requested as well as a maximum level for requested budgets. Only
limited budgetary information is required under this approach.  The
just-in-time concept allows applicants to submit certain information only when
there is a possibility for an award. It is anticipated that these changes will
reduce the administrative burden for the applicants, reviewers and Institute
staff.  The research grant application form PHS 398 (rev. 4/98) is to be used
in applying for  these grants, with the modifications noted below.

BUDGET INSTRUCTIONS

Modular Grant applications  will request direct costs in $25,000 modules, up
to a total direct cost request of $250,000 per year. (Applications that
request more than $250,000 direct costs in any year must follow the
traditional PHS 398 application instructions.)The total direct costs must be
requested  in accordance with the  program guidelines and  the modifications
made to the standard  PHS 398 application  instructions described below:

PHS 398

o  FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in
$25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total
Direct plus Facilities and Administrative  (F&A) costs] for the initial budget
period Items 8a and 8b should be completed indicating the Direct and Total
Costs for the entire proposed period of support.

o  DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4
of the PHS 398. It is not required and will not be accepted with the
application.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the
categorical budget table on Form Page 5 of the PHS 398. It is not required and
will not be accepted with the application.

o  NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample
pages) At the top of the page, enter the total direct costs requested for each
year.  This is not a Form page.

o  Under Personnel, List key project personnel, including their names, percent
of effort, and roles on the project. No individual salary information should
be provided. However, the applicant should use the NIH appropriation language 
salary cap and the NIH policy for graduate student compensation in developing
the budget request.

For Consortium/Contractual costs, provide an estimate of total costs (direct
plus facilities and administrative) for each year, each rounded to the nearest
$1,000.  List the individuals/organizations with whom consortium or
contractual arrangements have been made, the percent effort of key personnel,
and the role on the project.  Indicate whether the collaborating institution
is foreign or domestic.  The total cost for a consortium/contractual
arrangement is included in the overall requested modular direct cost amount. 
Include the letter of intent to establish a consortium.

Provide an additional narrative budget justification for any variation in the
number of modules requested.

o  BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by 
reviewers in the assessment of each individual's qualifications for a specific
role in the proposed project, as well as to evaluate the overall
qualifications of the research team. A biographical sketch is required for all
key personnel, following the instructions below. No more than three pages may
be used for each person.  A sample biographical sketch may be viewed at:
http://grants.nih.gov/grants/funding/modular/modular.htm

- Complete the educational block at the top of the form page;
- List position(s) and any honors;
- Provide information, including overall goals and responsibilities, on
research projects ongoing or completed during the last three years.
- List selected peer-reviewed publications, with full citations;

o  CHECKLIST - This page should be completed and submitted with the
application.  If the F&A rate agreement has been established, indicate the
type of agreement and the date.  All appropriate exclusions must be applied 
in the calculation of the F&A costs for the initial budget period and all
future budget years.

o  The applicant should provide the name and phone number of the individual to
contact concerning fiscal and administrative issues if additional information
is necessary following the initial review.

R01 applications that request more than $250,000 direct costs per year should
follow the instructions in the PHS Form 398.

The title and number of the program announcement must be typed on line 2 of
the face page of the application form and the YES box must be marked.

Submit a signed, typewritten original of the application, including the
Checklist, and five signed, photocopies, in one package to:

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established PHS referral
guidelines. Applications will be evaluated for scientific and technical merit
by an appropriate scientific review group convened in accordance with the
standard NIH peer review procedures. As part of the initial merit review, all
applications will receive a written critique and undergo a process in which
only those applications deemed to have the highest scientific merit, generally
the top half of applications under review, will be discussed, assigned a
priority score, and receive a second level review by the appropriate national
advisory council or board.

Review Criteria

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In
the written comments reviewers will be asked to discuss the following aspects
of the application in order to judge the likelihood that the proposed research
will have a substantial impact on the pursuit of these goals.  Each of these
criteria will be addressed and considered in assigning the overall score,
weighting them as appropriate for each application.  Note that the application
does not need to be strong in all categories to be judged likely to have major
scientific impact and thus deserve a high priority score.  For example, an
investigator may propose to carry out important work that by its nature is not
innovative but is essential to move a field forward.

(1) Significance:  Does this study address an important problem? If the aims
of the application are achieved, how will scientific knowledge be advanced? 
What will be the effect of these studies on the concepts or methods that drive
this field?

(2) Approach:  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

(3) Innovation:  Does the project employ novel concepts, approaches or method?
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

(4) Investigator:  Is the investigator appropriately trained and well suited
to carry out this work?  Is the work proposed appropriate to the experience
level of the principal investigator and other researchers (if any)?  Are the
nature and quality of the collaborations appropriate for the proposed
research?

(5) Environment:  Does the scientific environment in which the work will be
done contribute to the probability of success?  Do the proposed experiments
take advantage of unique features of the scientific environment or employ
useful collaborative arrangements?  Is there evidence of institutional
support?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o  The adequacy of plans to include both genders, minorities and their
subgroups, and children as appropriate for the scientific goals of the
research.  Plans for the recruitment and retention of subjects will also be
evaluated.

o  The reasonableness of the proposed budget and duration in relation to the
proposed research

o  The adequacy of the proposed protection for humans, animals or the
environment, to the extent they may be adversely affected by the project 
proposed in the application.

The initial review group will also examine the provisions for the protection
of human subjects and the safety of the research environment.

AWARD CRITERIA

Applications will compete for available funds with all other recommended
applications.  The following will be considered in making funding decisions:
Quality of the proposed project as determined by peer review, availability of
funds, and program priority.

INQUIRIES

Inquiries are encouraged.  The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Irene Anne Eckstrand, Ph.D.
Division of Genetics and Developmental Biology
National Institute of General Medical Sciences
Building 45, Room 2AS.25K, MSC 6200
Bethesda, MD  20892-6200
Telephone:  (301) 594-0943
FAX:  (301) 480-2228
Email:  Irene_Eckstrand@nih.gov

Dennis Mangan, Ph.D.
Division of Extramural Research
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN.32F, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-2421
FAX:  (301) 480-8318
Email:  Dennis.Mangan@nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Marcia Cohn
Grants Management Office
National Institute of General Medical Sciences
Building 45, Room 2AN.44E
Bethesda, MD  20892-6200
Telephone:  (301) 594-3918
FAX:  (301) 480-1969
Email:  cohnm@nigms.nih.gov

Daniel Milstead
Division of Extramural Research
National Institute of Dental and Craniofacial Research
Building 45, Room 4AN.44, MSC 6402
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
Email:  Daniel.Milstead@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.862.  Awards are made under authorization of the Public Health Service Act,
Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC
241 and 285) and administered under PHS grants policies and Federal
Regulations 42 CFR 52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372 or Health
Systems Agency review.

The PHS strongly encourages all grant and contract recipients to provide a
smoke-free workplace and promote the non-use of all tobacco products.  In
addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking
in certain facilities (or in some cases, and portion of a facility) in which
regular or routine education, library, day care, health care or early
childhood development services are provided to children.  This is consistent
with the PHS mission to protect and advance the physical and mental health of
the American people.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, RealPlayer, Video or Flash files, see Help Downloading Files.