Full Text PA-97-061
NIH GUIDE, Volume 26, Number 17, May 23, 1997
PA NUMBER:  PA-97-061
P.T. 34

  Diabetic Retinopathy 
  Biology, Cellular 
  Biology, Molecular 

National Eye Institute
The National Eye Institute (NEI) and the Juvenile Diabetes Foundation
International (JDFI) participate in an ongoing cooperative program of
research support.  The purpose of this effort is to stimulate basic
cellular and molecular biological research on diabetic retinopathy.
Applications submitted to the NIH will be assigned and reviewed
according to the usual NIH peer review procedures.  Meritorious
applications not funded by the NEI may be considered by the JDFI for
possible funding. Although not participating in this specific
program, the National Institute of Diabetes and Digestive and Kidney
Diseases continues to have a strong interest in the retinal
complications of diabetes as indicated by its support of The Diabetes
Control and Complications Trial and a study entitled the Epidemiology
of Diabetes Intervention and Complications, which have diabetic
retinopathy as one of their outcome measures.
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 program
announcement, Cooperative Program for Research on Diabetic
Retinopathy, is related to the priority area of reducing blindness
among people with diabetes.  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).
Applications may be submitted by domestic and foreign for-profit and
non-profit organizations, public and private, such as universities,
colleges, hospitals, laboratories, units of State and local
governments, and eligible agencies of the Federal government.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards.  Applications from
minority individuals and women are encouraged.
The mechanism of NEI support for this program will be the research
project grant (R01) or FIRST (R29) award.  The NEI and the JDFI plan
to make several awards each year.  With respect to post-award
administration, the current policies and requirements that govern the
research grant programs of the NIH and the JDFI will prevail
depending on the funding source.  Applicants should note that awards
made by the JDFI will be subject to the JDFI indirect cost policy.
The purpose of this NEI/JDFI cooperative program is to accelerate
basic research activities directed toward discovering the cellular
and molecular basis of diabetic retinopathy.  Recent advances in
structural, cell, and molecular biology can be applied more widely to
gain a better understanding of retinal cell basement membrane
biology, pericyte-endothelial cell interactions, three-dimensional
structure of retinal enzymes, and regulation of retinal gene
expression.  More information about retinal metabolic pathways and
how these pathways are regulated could possibly lead to the
development of biological modifiers or pharmacologic agents that
would be useful in preventing or treating diabetic retinopathy.
Diabetes can lead to changes in the permeability of the retinal
vasculature resulting in retinal edema and blurring of vision.  In
more advanced cases of diabetic retinopathy, retinal
neovascularization can lead to leakage of blood into the retina,
retinal detachment, with consequent catastrophic loss of vision.
While great strides have been made in the treatment of diabetic
retinopathy through such clinical trials as the Diabetic Retinopathy
Study, the Early Treatment of Diabetic Retinopathy Study, and the
Diabetic Retinopathy Vitrectomy Study, more research is needed on
basic cellular and molecular mechanisms of disease.
Studies in experimental animals point to elevated blood glucose
levels as important in the pathogenesis of diabetic retinopathy.
Laboratory investigations employing cultured cells show that elevated
glucose levels affect the metabolism and growth of pericytes,
capillary endothelial cells, and retinal pigment epithelial cells.
However, the fundamental mechanisms which cause diabetic retinopathy
remains unknown.  One hypothesis is that increased levels of
intracellular sorbitol are generated from glucose via the polyol
pathway by the enzyme aldose reductase.  Altered sorbitol levels in
turn may affect important cellular metabolites such as myoinositol
and the functioning of enzymes such as sodium-potassium ATPase.
Another hypothesis is that elevated glucose levels activate protein
kinase C (PKC) in the retina and may mediate some of the vascular
complications of diabetes.  A co-culture system of endothelial cells
and pericytes has been used to demonstrate that pericytes inhibit
growth of capillary endothelial cells, putatively through activation
of transforming growth factor beta.  Other work has shown that both
acidic and basic fibroblast growth factors can stimulate the
formation of new blood vessels in vivo.  A wide variety of other
growth factors have been implicated as possible causal agents of
retinal neovascularization.  These include growth hormone,
insulin-like growth factors, and insulin.  Endothelin-1, a potent
vasoconstrictor, is secreted by endothelial cells and binds to a high
affinity binding site on retinal pericytes.  This binding can be
decreased by elevated glucose levels. Cultured vascular cells or
pericytes exposed to high glucose levels show increased levels of
mRNA for collagen IV and fibronectin.  However, while there is
documented evidence of retinal vascular cell response to high levels
of glucose, the fundamental mechanisms that lead to diabetic
retinopathy remain to be determined.
The NEI and the JDFI plan to sponsor periodic meetings to facilitate
exchange of information among investigators funded as a result of
this initiative and to foster collaborative efforts among
investigators.  For this purpose, requests for travel funds for a
two-day meeting each year, in Bethesda, Maryland, should be included
in the budget.
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.
Application kits are available at most institutional offices of
sponsored research and may be obtained from the Division of
Extramural Outreach and Information Resources, National Institutes of
Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD  20882-7910,
telephone (301) 435-0714, Email:  ASKNIH@ODROCKM1.OD.NIH.GOV.  The
title "Cooperative Program for Research on Diabetic Retinopathy" must
be typed in Item 2 on the face page of the application.  Check the
"YES" box.
Applications for the FIRST award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
Submit the completed original application and five exact copies to:
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier / overnight service)
Applicants responding to this program announcement must submit a
brief letter as part of the application indicating whether or not
they wish their application to be considered for funding by the JDFI.
Letters of authorization should be prepared by the Principal
Investigator and co-signed by the appropriate official of the
applicant organization.  Applicants wishing to have their
applications considered by the JDFI must specifically authorize the
NEI to provide a copy of their application and the NIH-prepared
summary statement of the initial review to the JDFI.
Applications will be assigned on the basis of established Public
Health Service referral guidelines.  Applications will be reviewed
for scientific and technical merit by the Initial Review Groups of
the Division of Research Grants, NIH, in accordance with the standard
peer review procedures.  Following initial scientific and technical
review, the applications assigned to the NEI will receive a second
level review by the National Advisory Eye Council.
The following will be considered in making funding decisions on
applications assigned to the NEI:
o  scientific and technical merit of the proposed project as
determined by peer review
o  relevance to NEI program priorities as identified in "Vision
Research - A National Plan: 1994-1998," and this announcement, and
o  availability of funds.
The NEI will make its funding decisions first.  Upon request (see
above), those applications not funded by the NEI will be considered
for funding by the JDFI.  If the JDFI makes an award, the applicant
will be notified directly by the JDFI.
Written and telephone inquires are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.
Direct inquires regarding scientific issues to:
Peter A. Dudley, Ph.D.
Division of Extramural Research
National Eye Institute
Executive Plaza South, Suite 350
6120 Executive Boulevard  MSC 7164
Rockville, MD  20892-7164
Telephone:  (301) 496-0484
FAX:  (301) 402-0528
Email:  pad@eps.nei.nih.gov
Direct inquires regarding fiscal matters to:
Ms. Margie Baritz
Division of Extramural Research
National Eye Institute
Executive Plaza South, Suite 350
6120 Executive Boulevard  MSC 7164
Rockville, MD  20892-7164
Telephone:  (301) 496-5884
FAX:  (301) 496-9997
Email:  meb@eps.nei.nih.gov
This program is described in the Catalog of Federal Domestic
Assistance No. 93.867, Vision Research.  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 as implemented through Department of Health and Human
Services regulations at 45 CFR part 100 or Health Systems Agency
The Public Health Service (PHS) 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 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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