PATHOGENESIS AND THERAPY OF COMPLICATIONS OF DIABETES

NIH Guide, Volume 26, Number 38, November 21, 1997

RFA:  DK-98-009

P.T.

National Institute of Diabetes and Digestive and Kidney Diseases
National Eye Institute
National Heart, Lung, and Blood Institute
National Institute on Aging
National Institute of Dental Research
National Institute of Neurological Disorders and Stroke

Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:  March 19, 1998

PURPOSE

The Institutes listed above invite investigator-initiated research grant
applications to study the mechanisms by which hyperglycemia results in the late
complications of diabetes and to apply this information to the development of
interventions to prevent, limit or reverse complications associated with type 1
diabetes.  The Request for Applications (RFA) addresses pathogenic mechanisms
common to the spectrum of complications of diabetes, as well as research directed
specifically at diabetic neuropathy and retinopathy, and macrovascular and oral
complications.  A complementary RFA (DK-98-001) is focused on mechanisms, genetic
determinants and interventions for diabetic nephropathy. A particular area of
scientific opportunity, which is emphasized in this RFA, is the role of growth
factors in the pathogenesis and/or therapy of complications of diabetes.  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, Pathogenesis and Therapy of
Complications of Diabetes, is related to the priority area of diabetes and
chronic disabling conditions.  Potential applicants may obtain a copy of "Healthy
People 2000" (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), Interactive Research Project Grant (IRPG), and
Exploratory/Developmental Research Grant (R21) award mechanisms. Guidelines for
preparing IRPG applications are available from the program official or from the
internet at: http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html.

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.

Applicants from institutions that 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.  If so, 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.

Applicants anticipating submitting IRPG applications or applicants requesting
more than $500,000 direct costs in any year should consult with the NIDDK Program
Official listed under INQUIRIES at an early opportunity.  Applicants must receive
permission from the NIDDK prior to the submission of an application requesting
more than $500,000 in direct costs per year for any year of the proposed study. 
NIDDK staff will coordinate consideration and acceptance of such large
applications by the staff of the appropriate Institute.

The total requested project period for an application submitted in response to
this RFA may not exceed three years.  Budget escalations in future years are
limited to three percent of recurring costs.  The anticipated award date is
September 30, 1998.  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 1998, $6 million will be committed to fund applications submitted in
response to this RFA.  It is anticipated that approximately 25 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

Prevention and treatment of chronic complications is a central therapeutic
problem in type 1 diabetes mellitus. In the United States, diabetes is the
leading cause of new blindness in people age 20-74, and accounts for 35% of all
new cases of end-stage renal disease.  Over 60% of people with diabetes are
affected by neuropathy, and accelerated lower extremity arterial disease in
conjunction with neuropathy makes diabetes account for 50% of all nontraumatic
amputations in the United States. In addition, macrovascular complications are
a major cause of morbidity and mortality in diabetes, particularly in individuals
with nephropathy.  Diabetes also confers a markedly increased risk of developing
oral complications.

The Diabetes Control and Complications Trial (DCCT) demonstrated that exposure
to glycemia as measured by mean glycated hemoglobin (HbA1c) is the dominant
predictor of retinopathy and nephropathy, and that intensive therapy reduced
appearance and progression of these complications by 45% to 78%.  Intensive
therapy did not significantly reduce macrovascular complications, although there
was a non-significant trend towards reduced risk.  However, many patients are not
able to achieve near euglycemia, providing an imperative to develop new
approaches to prevent or ameliorate complications.

Several mechanisms by which hyperglycemia may damage cells and tissues have been
identified.  These include increased polyol pathway activity and associated
changes in intracellular redox state, increased diacylglycerol synthesis with
consequent activation of specific protein kinase C (PKC) isoforms, increased
nonenzymatic glycation of both intracellular and extracellular proteins, and
increased formation of reactive oxygen species.  Tissue injury then results from
acute changes in protein function and chronic changes in gene expression.  It is
likely that the pathologic effectors induced in different tissues by these
mechanisms are specific for each particular complication (e.g., VEGF in diabetic
retinopathy and TGF-beta in diabetic nephropathy). Evidence that abnormal PKC
activation, abnormal protein glycation and increased flux through the polyol
pathway play prominent roles in the pathogenesis of complications is particularly
strong in animal models, since a specific PKC isoform inhibitor prevents
diabetes-induced changes in retinal blood flow and glomerular filtration rate,
while an inhibitor of advanced glycation product formation prevents retinal
acellular capillary formation and increased mesangial volume.  Both agents
prevent diabetes-induced albuminuria.  Similarly, treatment with an aldose
reductase inhibitor prevents nerve conduction velocity slowing.  Antioxidants
such as vitamin E and lipoic acid also partially prevent several early vascular
and neurological abnormalities in diabetic animals.

Although much progress has been made, the possible interrelationships between
these various hyperglycemia- accelerated pathways have not been systematically
studied.  Different mechanisms may play a dominant role at different stages or
in different cell types or target tissues.  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 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.

Investigators may wish to make use of samples (plasma, serum, urine) from the
1441 subjects with type 1 diabetes enrolled in the DCCT and followed for a mean
of 6.5 years for the appearance and progression of retinopathy and other
complications.  For further information on this resource, see the Notice of
Availability of Biologic Samples from Diabetic Study Population which appeared
in the January 10, 1997 NIH Guide.

Examples that illustrate areas to be considered within the intent of this
solicitation are presented below.  The following examples are intended only to
provide a broad direction and should be considered illustrative, and not
restrictive:

o  Determine the sequence of events in the pathogenesis of hyperglycemia-induced
injury so that potential sites for intervention in this chain of events can be
identified

o  Examine the molecular and cellular mechanisms by which hyperglycemia mediates
its adverse effects and the interrelationships among these mechanisms, including:
increased polyol pathway flux, alterations of intracellular redox state,
oxidative stress, glycation of structural and functional proteins, altered
expression of growth factors, enhanced activity of PKC, impaired synthesis of
nitric oxide and vasoactive prostacyclins, and altered metabolism of fatty acids

o  Define the mechanisms by which the biochemical changes resulting from
hyperglycemia mediate functional changes, such as altered blood flow, and
anatomical changes

o  Define the utility (alone or in combination) and mechanisms of action in
preventing or attenuating cell and tissue damage and neural dysfunction of
aminoguanidine, antioxidants, transition metal chelators, aldose reductase
inhibitors, PKC beta isoform inhibitors, nitrovasodilators, essential fatty
acids, prostacyclin analogs, human C-peptide, and other potential therapeutic
agents

o  Develop novel agents which may be effective in preventing or attenuating
complications such as modulators of growth factor expression or activity, or
inhibitors targeting discrete steps of the glycation pathway

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

o  Identify genetic modulators of the susceptibility of tissues to hyperglycemia-
induced injury

o  Develop surrogate endpoints (intermediate phenotypes) to identify subjects for
genetic analysis

o  Develop methods to measure microvascular function, examine capillary
permeability, identify the initial vascular cell responses to hyperglycemia, and
detect accelerated endothelial cell death before the development of morphological
abnormalities

o  Define the mechanisms by which PKC activation modulates processes involved in
complications, including vascular cell growth, permeability and gene expression

o  Determine how advanced glycation end product (AGE) accumulation could lead to
cellular injury and widespread tissue dysfunction, by delineating AGE's effects
on vascular matrix, permeability and/or relaxation, growth factor expression,
inflammatory responses, and cellular activation and function

o  Identify the mechanisms and biochemical and genetic components involved in
basement membrane thickening in diabetes

o  Elucidate the initiating mechanism for injury in experimental diabetic
retinopathy

o  Identify the chain of events leading to increased VEGF production in vivo in
proliferative retinopathy

o  Develop and study models useful for investigating the effects of VEGF on
vascular leakage and neovascularization, and for identifying inhibitors of ocular
neovascularization

o  Develop VEGF inhibitors or other methods of reducing the bioavailability of
VEGF

o  Study the role of growth hormone and other growth factors in the pathogenesis
of diabetic retinopathy

o  Investigate the fundamental molecular and cellular mechanisms involved in
hyperglycemia-induced nerve dysfunction

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  Develop methods for targeted delivery of neurotropins

o  Define the role of microangiopathy in the pathogenesis of diabetic neuropathy

o  Define the mechanisms by which metabolic changes of diabetes exert a negative
impact on nerve blood supply

o  Identify mechanisms by which hyperglycemia increases mammalian nerve oxidative
stress, including hyperglycemic autoxidation-glycation and endoneurial lipid
peroxidation

o  Develop improved methods to characterize and quantitate diabetic neuropathy
in humans and animal models that can serve as standardized surrogate endpoints
or outcome measures in clinical and animal studies

o  Determine ways in which hyperglycemia can produce vascular injury that may
initiate or accelerate macrovascular complications of diabetes

o  Develop therapeutic strategies, independent of glucose, hypertension or lipid
control, to block the effects of sustained hyperglycemia on progression of
atherosclerosis

o  Study the effect of growth factors on the progression of macrovascular
complications of diabetes looking for common and dissimilar effects from those
involved in the pathogenesis of diabetic microvascular complications

o  Determine the mechanisms by which hyperglycemia and growth factors cause oral
complications of diabetes, including effects on oral connective, vascular and
neural tissues

o  Study effects of age-related physiologic changes on the rates of progression
of complications of type 1 diabetes, and their underlying mechanisms.

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.

LETTER OF INTENT

Prospective applicants are asked to submit by February 19, 1998, 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 NIDDK staff to estimate the potential review workload and avoid conflict
of interest in the review.

The letter of intent is to be sent to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F - MSC 6600
BETHESDA, MD  20892-6600
Telephone:  (301) 594-8885
FAX:  (301) 480-3505

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) 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: 
ASKNIH@od.nih.gov.

The RFA label available in the PHS 398 (rev. 5/95) 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.

As indicated under MECHANISM OF SUPPORT, if a collaboration (IRPG) of individual
investigators is planned, it is necessary to identify one of the investigators
as the group coordinator and to cite this individual in all applications on page
2 of the form PHS 398 (rev. 5/95).  Applicants who have entered into a
collaboration may submit the applications individually with a cover letter noting
their involvement and listing the other members of the collaboration.

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, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AS-37F - MSC 6600
BETHESDA, MD 20892-6600

Applications must be received by March 19, 1998.  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

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

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 and minorities and their subgroups
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.

IRPG applications will have these additional review criteria:

o  Each component R01 of the IRPG will be reviewed as above for its independent
scientific merit.

o  The reviewers will assess the intended IRPG interactions, including the
effectiveness and feasibility of the proposed IRPG group interactions, whether
or not they enhance the prospects for reaching the stated objectives of the
group, and the extent of synergy among the various projects.

AWARD CRITERIA

The anticipated date of award is September 30, 1998.

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.

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:

Judith Fradkin, M.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 5AN-12E - MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8814
FAX:  (301) 480-3503
Email:  jf58s@nih.gov

Peter A. Dudley, Ph.D.
Vision Research Program
National Eye Institute
Executive Plaza South, Room 350
Bethesda, MD  20892
Telephone:  (301) 496-0484
FAX:  (301) 402-0528
Email:  pad@nei.nih.gov

Peter J. Savage, M.D.
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 8104
Bethesda, MD  20892-7938
Telephone:  (301) 435-0421
FAX:  (301) 480-5298
Email:  ps47h@nih.gov

Pamela E. Starke-Reed,  Ph.D.
Office of Nutrition
National Institute on Aging
Gateway Building, Room 2C231
Bethesda, MD  20892-9205
Telephone:  (301) 496-6402
FAX:  (301) 402-0010
Email:  PS39P@NIH.GOV

Dennis Mangan, Ph.D.
Division of Extramural Research
National Institute of Dental Research
Natcher Building, Room 4AN-32F
Bethesda, MD  20892-6402
Telephone:  (301) 594-2421
FAX:  (301) 480-8318
Email:  ManganD@de45.nidr.nih.gov

Paul L. Nichols, Ph.D.
Division of Convulsive, Infectious, and Immune Disorders
National Institute of Neurological Disorders and Stroke
Federal Building, Room 504
Bethesda, MD  20892
Telephone: (301) 496-1431
FAX:  (301) 402-2060
Email:  pn13w@nih.gov

Direct inquiries regarding fiscal and administrative matters to:

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

Margie Baritz
Division of Extramural Activities
National Eye Institute
Executive Plaza South, Room 350
Bethesda, MD  20892-6600
Telephone:  (301) 496-5884
FAX:  (301) 496-9997
Email:  Mbaritz@nei.nih.gov

William Darby
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7128
Bethesda, MD  20892-7128
Telephone:  (301) 435-0177
FAX:  (301) 480-3310
Email:  William_Darby@nih.gov

Robert Pike
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Room 2N212
Bethesda, MD  20892-9205
Telephone:  (301) 496-1472
Email:  Pikeb@exmur.nia.nih.gov

Martin R. Rubinstein
Division of Extramural Research
National Institute of Dental Research
Building 45, Room 4AN-44A
Bethesda, MD  20892-6402
Telephone:  (301) 594-4800
Email:  Martin.Rubinstein@nih.gov

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

SCHEDULE

Letter of Intent Receipt Date:  February 19, 1998
Application Receipt Date:       March 19, 1998
Initial Review:                 June/July 1998
Second Level Review:            September 1998
Anticipated Date of Award:      September 30, 1998

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.847 ("Diabetes, Endocrinology and Metabolic Diseases), 93.867 ("Vision
Research"), 93.387 ("Heart and Vascular Disease"), 93.866 ("Aging Research"),
93.121 ("Oral Diseases and Disorders Research Awards"), 93.853 ("Clinical
Research Related Neurological Disorders"), 93.854 ("Biological Basis Research in
the Neurosciences").  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, 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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