NEUROBIOLOGY OF DIABETIC COMPLICATIONS

Release Date:  January 13, 2000

RFA:  NS-00-002

National Institute of Neurological Disorders and Stroke
National Institute of Diabetes and Digestive and Kidney Diseases
Juvenile Diabetes Foundation International

Letter of Intent Receipt Date:  March 24, 2000
Application Receipt Date:  April 25, 2000

THIS RFA 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 
RFA/PA.

PURPOSE

The National Institute of Neurological Diseases and Stroke (NINDS), the 
National Institute of Diabetes and Digestive and Kidney Diseases 
(NIDDK), and the Juvenile Diabetes Foundation International (JDF) 
invite investigator-initiated research grant applications to study the 
neurobiology of diabetic complications. Research should be aimed at 
understanding the mechanisms by which diabetes results in painful, 
disabling peripheral neuropathy, autonomic neuropathy, impaired 
counterregulation and hypoglycemia unawareness, and other neurological 
complications. The intent of this RFA is to attract basic 
neuroscientists to the study of diabetic neuropathy and neurobiology 
relevant to diabetes, and enhance interdisciplinary approaches to 
research in this area.

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 RFA, 
Neurobiology of Diabetic Complications, is related to the priority area 
of diabetes and chronic diseases. Potential applicants may obtain a 
copy of "Healthy People 2000" at 
http://odphp.osophs.dhhs.gov/pubs/hp2000/

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign for-profit and 
nonprofit organizations, public and private, such as universities, 
colleges, hospitals, laboratories, units of State and local 
governments, and eligible agencies of the Federal government. 
Racial/ethnic minority individuals, women, and persons with 
disabilities are encouraged to apply as principal investigators.


MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research 
project grant (R01) and the Exploratory/Development Research Grant 
(R21) award mechanisms. 

The R21 awards are to demonstrate feasibility and to obtain preliminary 
data testing innovative ideas that represent clear departure from 
ongoing research interests. These grants are intended to 1) provide 
initial support for new investigators; 2) allow exploration of possible 
innovative new directions for established investigators; and 3) 
stimulate investigators from other areas to lend their expertise to 
research within the scope of this solicitation. Applicants for the R21 
must limit their requests to $100,000 direct costs per year and are 
limited to two years. These R21 grants will not be renewable; 
continuation of projects developed under this program will be through 
the
regular research grant (R01) program.

Except as otherwise stated in this announcement, awards will be 
administered under  grants policy as stated in the NIH Grants Policy 
Statement.

Applicants from institutions which have a General Clinical Research 
Center (GCRC) funded by the NIH National Center for Research Resources 
may wish to identify the GCRC as a resource for conducting the proposed 
research. In such a case, a letter of agreement from either the GCRC 
program director or principal investigator should be included with the 
application. 

This RFA is a one-time solicitation. Future unsolicited competing 
continuation applications will compete with all investigator-initiated 
applications and be reviewed according to the customary peer review 
procedures. Responsibility for the planning, direction, and execution 
of the proposed project will be solely that of the applicant. The 
anticipated award date is September 29, 2000. 

FUNDS AVAILABLE

The NINDS and NIDDK intend to commit up to $3 million in FY 2000 to 
fund 15 to 20 new and/or competitive continuation grants in response to 
this RFA. The JDF intends to commit up to $1M in additional funds to 
co-fund research project grants that are both scientifically 
meritorious and fit within the mission and research emphasis areas of 
the JDF. (See http://www.jdfcure.org, for more information.). All 
awards will be issued by the NINDS and the NIDDK. An applicant may 
request a project period of up to 5 years for an R01. Because the 
nature and scope of the research proposed may vary, it is anticipated 
that the size of each award will also vary. Although the financial 
plans of the NINDS, NIDDK, and JDF provide support for this program, 
awards pursuant to this RFA are contingent upon the availability of 
funds and the receipt of a sufficient number of applications of 
outstanding scientific and technical merit. 

RESEARCH OBJECTIVES

Background

Over 60 per cent of individuals with diabetes suffer from some form of 
neuropathy, and in many patients the symptoms are serious enough to 
interfere with daily activities. Small nerve fiber dysfunction 
typically occurs first in the lower extremities, where it is manifest 
by loss of thermal sensitivity and pin prick; pain and paresthesis are 
often present. Large fiber damage is characterized by reduced vibration 
perception, light touch and position sense, as well as weakness and 
depressed tendon reflexes. Diabetic peripheral neuropathy is often 
associated with peripheral vascular disease and impaired wound healing, 
resulting in more than 200,000 cases of foot ulcers and 80,000 
amputations per year, with an annual medical cost of over $2 billion. 
In fact, diabetes is the leading cause of non-traumatic lower leg 
amputations in the United States. Symptoms of diabetic autonomic 
neuropathy can include heart rate abnormalities, blood pressure 
dysregulation, dizziness, digestive disturbances, and impotence. 
Autonomic neuropathy is thought to be an important cause of sudden 
cardiac death in patients with diabetes. Effective therapies for the 
prevention and treatment of diabetic neuropathy are not currently 
available.

The Diabetes Control and Prevention Trial (DCCT) in patients with type 
1 diabetes, and the United Kingdom Prospective Diabetes Study (UKPDS) 
in type 2 diabetics have conclusively demonstrated that good glucose 
control significantly reduces the incidence of microvascular 
complications. With current treatment modalities, however, tight 
control remains an unattainable goal for many people with diabetes. In 
addition, metabolic abnormalities may impair neuronal function and lead 
to hypoglycemia unawareness, which limits the ability of a patient to 
undertake intensive insulin therapy. Thus, it is imperative that new 
approaches to prevent or ameliorate complications be developed.

To design new, effective therapeutic modalities it is essential to 
understand the molecular basis for hyperglycemia-induced nerve damage. 
Mechanisms by which nerves may be injured in diabetes include 
microvascular compromise, demyelination, apoptosis, and altered 
metabolism. In the past, attention has been focused on hyperglycemia-
induced changes in metabolism, including the induction of the polyol 
pathway, alterations in intracellular redox state, hyperosmolarity, 
abnormal PKC activation and glycation of proteins. Abnormalities in 
various neurotrophic factors have also been implicated in the 
development of diabetic neuropathy. 

Despite the progress that has been made in this area, the 
interrelationships between the various mechanisms of injury have not 
been systematically studied. Different mechanisms may play a dominant 
role at different stages of neuronal damage. The molecular basis for 
many of the relevant signaling pathways remains unknown. In addition, 
there have been significant advances in the realm of basic neurobiology 
that need to be studied in the context of diabetes. Relevant advances 
include research relating to apoptosis, neuronal regeneration, Schwann-
axon cell interactions, neurotrophins, and the role of the vasculature 
in supporting neuronal function.

Scope and Objectives

The major focus of this RFA is to apply recent advances in the 
neurosciences to the study of the neurological complications of 
diabetes. Investigators with diverse scientific interests are invited 
to apply their expertise to basic and applied research to enhance our 
understanding of the pathogenesis of diabetic neuropathy, to develop 
appropriate models relevant to understanding and treating these 
complications, and to develop innovative strategies to prevent, limit, 
or reverse these complications. Applications may focus on peripheral 
neuropathy, autonomic neuropathy and/or hypoglycemia unawareness. It is 
highly desirable for basic neurobiologists to form collaborative 
efforts with diabetologists. Appropriate topics for investigation would 
include but are not limited to:

o Studies of abnormalities in peripheral nervous system myelin 
synthesis, structure, and function in diabetic neuropathy

o Studies of perturbations in end-organ/axonal trophic interactions in 
diabetic neuropathy

o Development of improved experimental models for study of diabetic 
neuropathy in animals and in vitro

o Studies of mechanisms involved in pain conditions associated with 
diabetic neuropathy and their relation to other neuropathic pain 
conditions

o Studies of the mechanism of action and efficacy of potential 
therapeutic agents to relieve pain associated with diabetic neuropathy

o Development of new non-invasive methods for early detection of 
neuropathy, which can function as surrogate endpoints for measuring the 
effectiveness of therapeutic interventions

o Studies to identify determinants of peripheral nerve regeneration and 
aborted regeneration in diabetes.

o Studies to define determinants of cell death of nerves or Schwann 
cells in diabetic neuropathy.

o Studies to delineate the role of growth factors and/or cytokines in 
the pathogenesis of diabetic neuropathy and their utility in the 
prevention or treatment of neuropathy.

o Studies to characterize the neuronal response to injury in diabetes.

o Studies to develop clinically useful, surrogate markers for C-fiber 
damage.

o Studies to evaluate diabetes-associated endothelial dysfunction in 
the vasa nervorum/endoneurium/perineurium.

o Studies to understand the non-myelin trophic support role of Schwann 
cells.

o Studies to define the role of peripheral nerves in regulating the 
biology of the epidermis and dermis.

o Studies to determine the biochemical mechanisms of nerve damage, 
focusing on hyperglycemia-induced abnormalities.

o Studies to determine the role of insulin in diabetic nerve damage.

o Studies of the role of diabetic neuropathy in silent cardiac ischemia 
and/or increased peri-infarction mortality in patients with diabetes.

o Studies to investigate the effect of abnormal glucose metabolism on 
hypothalamic and/or other CNS circuits that regulate autonomic function 
and detection of hypoglycemia.

o Studies of the role of the nervous system in endocrine responses to 
hypoglycemia and how diabetes may alter the counterregulatory response.

o Studies to determine the role of autonomic neuropathy in hypoglycemia 
unawareness.

SPECIAL REQUIREMENTS

Letter of Authorization

Applicants should submit a brief letter to the NINDS indicating whether 
or not they wish their application to be considered for funding by the 
JDF. While applicants may request that their applications be considered 
only by the NIH and not by the JDF, it is necessary that the record 
indicate the applicant's consideration of this opportunity. For those 
applicants who wish to have the JDF consider their application, all 
materials relating to the application will be promptly forwarded to 
that organization and the summary statements for such applications will 
be shared with the JDF when available. This separate letter may be 
submitted with the Letter of Intent (see below).

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 was published in the Federal 
Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide For 
Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the 
web at: 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 Subjects” 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 may also obtain copies of these policies from the program 
staff listed under INQUIRIES. Program staff may also provide additional 
relevant information concerning the policy.

LETTER OF INTENT 

Prospective applicants are asked to submit, by March 24, 2000, a letter 
of intent that includes a descriptive title of the proposed research; 
the name, address, and telephone number of the Principal Investigator; 
the identities of other key personnel and participating institutions; 
and the number and title of the RFA in response to which the 
application may be submitted.

Although a letter of intent is not required, is not binding, and does 
not enter into the review of a subsequent application, the information 
that it contains allows NINDS staff to estimate the potential review 
workload and avoid conflict of interest in the review.

The letter of intent is to be mailed, faxed, or sent by e-mail to:

Paul L. Nichols, Ph.D.
NINDS
Neuroscience Center, Room 2118
6001 Executive Blvd.
Bethesda, MD 20892
Telephone: (301) 496-9964
FAX: (301) 402-2060
E-mail:  pn13w@nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used 
in applying for these grants. These forms 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.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. The 
program announcement title and number must be typed on line 2 of the 
face page of the application form and the YES box must be marked.

The RFA label available in the PHS 398 (rev. 4/98) application form 
must be affixed to the bottom of the face page of the application with 
the RFA number on label. Failure to use this label could result in 
delayed processing of the application such that it may not reach the 
review committee in time for review. In addition, the RFA title and 
number must be typed on line 2 of the face page of the application form 
and the YES box must be marked.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been  
modified  to allow for this change.  Please note this is in pdf format.
 
Submit a signed, typewritten original of the application, including the 
Checklist, and three 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)

At time of submission, two additional copies of the application must be 
sent to:

Chief, Scientific Review Branch
Division of Extramural Activities, NINDS
Neuroscience Center, Room 3208
6001 Executive Blvd.
Bethesda, MD 20892

Applications must be received by the application receipt date listed in 
the heading of the RFA. If an application is received after that date, 
it will be returned to the applicant without review. Supplemental 
documents containing significant revision or additions will not be 
accepted, unless applicants are notified by the Scientific Review 
Administrator. 

The Center for Scientific Review (CSR) will not accept any application 
in response to this RFA that is essentially the same as one currently 
pending initial review, unless the applicant withdraws the pending 
application. The CSR will not accept any application that is 
essentially the same as one already reviewed. This does not preclude 
the submission of substantial revisions of applications previously 
reviewed, but such applications must include an introduction addressing 
the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NINDS and NIDDK. Incomplete and/or non-
responsive applications will be returned to the applicant without 
further consideration. 

Applications that are complete and responsive to the RFA will be 
evaluated for scientific and technical merit by an appropriate peer 
review group convened by the NINDS in accordance with the review 
criteria stated below. 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 the applications under review, will be 
discussed, assigned a priority score, and receive a second level review 
by the Advisory Councils of NINDS and NIDDK.

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, reviewer 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)?

(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 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 to the 
proposed research.

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

o Availability of special opportunities for furthering research 
programs through the use of unusual talent resources, populations, or 
environmental conditions in other countries which are not readily 
available in the United States or which provide augmentation of 
existing U.S. resources.

Schedule
Letter of Intent Receipt Date: March 24, 2000 
Application Receipt Date: April 25, 2000 
Peer Review Date: July/August 2000 
Council Review: September 2000 
Earliest Anticipated Start Date: September 29, 2000 

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit as determined by peer review;

o Availability of funds;

o Programmatic priorities.

INQUIRIES

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

Direct inquiries regarding programmatic issues to:

Paul L. Nichols, Ph.D.
NINDS
Neuroscience Center, Room 2118
6001 Executive Blvd.
Bethesda, MD 20892
Telephone: (301) 496-9964
FAX: (301) 402-2060
E-mail: pn13w@nih.gov

Barbara Linder, M.D., Ph.D. 
DDEMD
NIDDK 
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-0021
FAX:  (301) 480-3503
E-mail:  linderb@extra.niddk.nih.gov

Direct inquiries regarding fiscal matters to:

Nancy Dixon
Division of Extramural Activities 
NIDDK
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8854 
FAX:  (301) 480-4237
E-mail:  dixonn@extra.niddk.nih.gov

Dawn Richardson
Grants Management Branch
NINDS
Neuroscience Center, Room 3254
6001 Executive Blvd.
Bethesda, MD 20892
Telephone: (301) 496-9231
FAX: (301) 402-0129
E-mail: da8h@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance 
No. 93.847, 
93. 853. Awards are 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 NIH grants policies and 
Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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, any 
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.

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