NEUROLOGICAL COMPLICATIONS OF DIABETES

Release Date:  December 22, 1998

RFA:  NS-99-005

P.T.

National Institute of Neurological Disorders and Stroke
National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date:  March 16, 1999
Application Receipt Date:  April 27, 1999

PURPOSE

The National Institute of Neurological Disorders and Stroke (NINDS) and the
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) invite
investigator-initiated research grant applications to study the mechanisms by
which diabetes results in painful and disabling neuropathies and other
neurological complications and to apply this information to the development of
interventions to prevent, limit, or reverse these complications.  The etiology
of diabetic neuropathy is complex, involving metabolic and vascular effects. 
Recent evidence suggests that deficiencies in neurotrophic factors may also play
a role.  Diabetic autonomic neuropathy is a particularly understudied area.  The
intent of this RFA is to intensify investigator-initiated research, to attract
new investigators to the field and to enhance interdisciplinary approaches to
research in these areas.

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, Neurological Complications of
Diabetes, is related to the priority area of diabetes and chronic disabling
conditions.  Potential applicants may access "Healthy People 2000" at:
http://odphp.osophs.dhhs.gov/pubs/hp2000/ or obtain a copy (Full Report: Stock
No. 017-001-00474-0 or Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington, DC 20402-
9325 (telephone: 202-512-1800).

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.  Racial/ethnic minority individuals, women, and persons with
disabilities are encouraged to apply as Principal Investigators.

MECHANISM OF SUPPORT

Support of this program will be through the National Institutes of Health (NIH)
Research Project Grant (R01) and Exploratory/Developmental Research Grant (R21)
award mechanisms.

The R21 awards are to demonstrate feasibility of a concept and to generate
sufficient preliminary data to pursue it through other funding mechanisms.  These
grants are intended to (1) provide initial support for new investigators; (2)
allow exploration of possible innovative new leads or 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.

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.

The total requested project period for an application submitted in response to
this RFA may not exceed four years.  Budget escalations in future years are
limited to three percent of recurring costs.  The anticipated award date is
September 30, 1999.  Responsibility for the planning, direction, and execution
of the proposed project will be solely that of the applicant.  Awards will be
administered under Public Health Service (PHS) grants policy as stated in the PHS
Grants Policy Statement.

FUNDS AVAILABLE

For FY 1999, $2.5 million will be committed to fund applications submitted in
response to this RFA.  It is anticipated that approximately 12 awards will be
made. However, this funding level is dependent upon the receipt of a sufficient
number of applications of high scientific merit.  The award of grants pursuant
to this RFA is also contingent upon the availability of funds for this purpose.

RESEARCH OBJECTIVES

Background

Neurological complications are central problems in diabetes mellitus.  Over 60%
of people with diabetes are affected by neuropathy, and in many patients symptoms
such as pain, numbness, weakness, or even paralysis are serious enough to
interfere with daily activities.  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.  Symptoms of diabetic autonomic
neuropathy can include heart rate abnormalities, hypertension, dizziness,
digestive disturbances, and impotence.  Autonomic neuropathy is an important
cause of sudden cardiac death in people with diabetes.  Prevention and treatment
are often ineffective.  New modalities are badly needed.

Mechanisms by which nerves may be injured in diabetes include microvascular
compromise (sensory-motor, cranial, autonomic neuropathies), segmental and
paranodal demyelination (symmetric, motor neuropathies), altered metabolism, and
possibly apoptosis.  Altered nerve metabolism related to hyperglycemia may
involve the polyol pathway, intracellular redox state, hyperosmolarity, and/or
glycation of structural and functional proteins.  In addition, abnormal fatty
acid metabolism, altered intracellular redox state, and abnormal PKC activation
may be involved.  Neurotrophic factors may be inadequate or relatively inactive. 
Several of these mechanisms have been shown to play prominent roles in animal
models of diabetes in which there is neuropathy.

The Diabetes Control and Complications Trial (DCCT) and a smaller Swedish study
have demonstrated that exposure to glycemia as measured by mean glycated
hemoglobin (HbA1c) is a predictor of neuropathy in type 1 diabetes, and that
intensive insulin therapy reduced appearance and progression of these
complications.  There is some evidence that aggressive insulin therapy may
achieve the same result in some type 2 patients as well.  Many patients, however,
are not able to achieve near euglycemia, providing an imperative to develop new
approaches to prevent or ameliorate complications.

Although much progress has been made, the possible interrelationships between
these various mechanisms of injury have not been systematically studied. 
Different mechanisms may play a dominant role at different stages.  Also,
development of interventions for modifying known pathways is limited, and many
molecular elements of relevant signaling pathways are unknown.

Scope and Objectives

Investigators with diverse scientific interests are invited to apply their
expertise to basic and applied research to enhance our understanding of the
pathogenesis of neurological complications of diabetes, to develop appropriate
models relevant to understanding and treating these complications, to develop
innovative strategies to prevent, limit or reverse these complications, and to
test new approaches to therapy.

Examples that illustrate areas to be considered within the intent of this
solicitation are presented below.  Studies of diabetic autonomic neuropathies are
especially encouraged.  The following examples should be considered illustrative
and not restrictive, and other innovative approaches are encouraged:

o  Define the role of microvascular angiopathies in the pathogenesis of diabetic
neuropathy.

o  Investigate the possible role of programmed cell death (apoptosis) of nerves
or Schwann cells in diabetes.

o  Investigate the mechanisms of demyelination which contribute to motor
neuropathies.

o  Delineate the role of NGF and other neurotrophic factors in pathogenesis of
diabetic neuropathy and their utility in prevention and amelioration of diabetic
neuropathy.

o  Examine the mechanisms by which hyperglycemia may mediate its adverse effects
and the interrelationships among these mechanisms.

o  Study mechanisms involved in the unique pain conditions associated with
diabetic neuropathy.

o  Identify genes that may be important in the prevention, causation, and/or
progression of diabetic neuropathy in humans, monkeys, and spontaneous rodent
models, and determine the function of these genes.

o  Develop transgenic and gene deletion animal models to elucidate the elements
involved in hyperglycemia-induced activation/inhibition of gene expression.

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

o  Identify protective factors in diabetic patients with no signs of neuropathy.

o  Study the mechanism of action and efficacy of potential therapeutic agents
such as aminoguanidine, antioxidants, transition metal chelators, aldose
reductase inhibitors, essential fatty acids, prostacyclin analogs, or other
agents.

o  Develop methods that will enhance regeneration of diseased peripheral and
autonomic nerves in diabetic individuals.

o  Explore the use of non-pharmacological therapies, such as laser exposure or
subsensory electrical stimulation.

o  Investigate hypothalamic and other central circuits that regulate autonomic
function and detection of metabolic imbalance.

o  Study the role of diabetic autonomic neuropathy in the inability to detect
symptoms of low blood sugar (hypoglycemia unawareness).

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
sub-populations 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.

Investigators may also obtain copies from these sources or from the program staff
or contact person listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.

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

LETTER OF INTENT

Prospective applicants are asked to submit by March 16, 1999, 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 this RFA. 
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 sent to:

Paul L. Nichols, Ph.D.
Division of Convulsive, Infectious, and Immune Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 504 MSC 9160
Bethesda, MD  20892-9160
Telephone:  (301) 496-1431
FAX:  (301) 401-2060
Email:  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; and are available on the internet at: 
http://grants.nih.gov/grants/forms.htm

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.  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.

Submit a signed, typewritten original of the application, including the
Checklist, plus 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
National Institute of Neurological Disorders and Stroke
Federal Building, Room 9C10A
BETHESDA, MD 20892

Applications must be received by April 27, 1999.  If an application is received
after that date, it will be returned to the applicant without review.  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 participating Institutes.  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 in
accordance with 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 will be
discussed, assigned a priority score, and receive a second level review by the
National Advisory Council of the assigned Institute(s).

Review Criteria

The goals of the supported research are to advance our understanding of
biological systems, improve the control of disease, improve health care services,
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.

o  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?

o  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?

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

o  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)?

o  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?

o  Appropriateness of the proposed budget and duration in relation to the
proposed research.

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 be evaluated.

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

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 United States resources.

o  For those applications that propose collaborative efforts between several
applicants, additional factors to be considered during the review would include
the efficacy of the collaboration, the commitment of the participants to the
collaboration, the design and responsibilities of the coordinating center and the
cost effectiveness of the collaborative effort.

R21 applications will have the additional review criteria:

o  Potential for novel and innovative approaches that clearly require additional
preliminary data for their value to be established.

AWARD CRITERIA

The anticipated date of award is September 30, 1999.

The factors that will be used to make award decisions include:

o  scientific and technical merit as determined by peer review,
o  availability of funds, and
o  programmatic priorities.

SCHEDULE

Letter of Intent Receipt Date:  March 16, 1999
Application Receipt Date:       April 27, 1999
Initial Review:                 July 1999
Second Level Review:            September 1999
Anticipated Date of Award:      September 30, 1999

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.
Division of Convulsive, Infectious, and Immune Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 504 - MSC 9160
Bethesda, MD  20892-9160
Telephone:  (301) 496-1431
FAX:  (301) 401-2060
Email:  pn13w@nih.gov

Barbara Linder, M.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 5AN18A
Bethesda, MD  20892
Telephone:  (301) 594-0021
FAX:  (301) 480-3503
Email:  bl99n@nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Dawn Richardson
Grants Management Branch
National Institute of Neurological Disorders and Stroke
Federal Building, Room 1004
Bethesda, MD  20892
Telephone: (301) 496-9231
FAX:  (301) 402-0219
Email:  da8h@nih.gov

Nancy C. Dixon
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8854
FAX:  (301) 480-4237
Email:  dixonn@extra.niddk.nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.853 and 93.854 for the NINDS and 93.847 for the NIDDK.  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.  Awards will be administered under
PHS grants policy as stated in the Public Health Service Grants Policy Statement
(April 1, 1994).

The Public Health Service strongly encourages all grant 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 for 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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