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 301-710-0267, 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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