NIH GUIDE, Volume 23, Number 3, January 21, 1994

PA NUMBER:  PA-94-028

P.T. 34


  Diabetic Retinopathy 

  Biology, Cellular 

  Biology, Molecular 

National Eye Institute


The National Eye Institute (NEI) and the Juvenile Diabetes Foundation

International (JDFI) have initiated a 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 continuing support of The Diabetes Control and

Complications Trial, which has diabetic retinopathy as one of its

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

"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)

through the Superintendent of Documents, Government Printing Office,

Washington, DC 20402-9325 (telephone 202/783-3238).


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 in FY 1994 and for several years

thereafter.  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. 9/91) 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 Office of Grants

Information, Division of Research Grants, National Institutes of

Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone

301/710-0267.  The title "Cooperative Program for Research on

Diabetic Retinopathy" must be typed in Section 2a on the face page of

the application.

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.

The completed original application and five exact copies must be

mailed or delivered to:

Division of Research Grants

National Institutes of health

Westwood Building, Room 240

Bethesda, MD  20892**


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.

Retinal Diseases Branch

National Eye Institute

Executive Plaza South, Suite 350

6120 Executive Boulevard

Rockville, MD  20892

Telephone:  (301) 496-0484

Direct inquires regarding fiscal matters to:

Ms. Margie Baritz

Division of Extramural Activities

National Eye Institute

Executive Plaza South, Suite 350

6120 Executive Boulevard

Rockville, MD  20892

Telephone:  (301) 496-5884


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.  Applications  are 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



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