THE ROLE OF GROWTH FACTORS IN THE DEVELOPMENT OF DIABETES COMPLICATIONS

Release Date: September 2, 1999

PA NUMBER:  PA-99-159

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

THIS PA USES THE "MODULAR GRANT" AND JUST-IN-TIME" CONCEPTS.  IT INCLUDES
DETAILED MODIFICATIONS TO THE STANDARD APPLICATION INSTRUCTIONS THAT MUST BE
USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PA.

PURPOSE

The National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK),
National Eye Institute (NEI), National Institute of Dental and Craniofacial
Research (NIDCR), National Institute of Neurological Disorders and Stroke
(NINDS), and National Heart, Lung, and Blood Institute invite investigator-
initiated research grant applications to study the role of growth factors in
the etiology and pathogenesis of the micro- and macrovascular complications of
diabetes.  While several growth factors are already being tested in clinical
trials for the treatment and/or prevention of diabetic  microvascular disease,
a systemic examination of the pathophysiologic role of growth factors in
diabetic complications is lacking.  This PA, with a $2 million NIDDK annual
set-aside, is intended to stimulate the application of new molecular
technologies to this area.  An understanding of the tissue and cell specific
expression of growth factors in the eye, kidney, mouth, nerves and vessels,
and of the molecular action of these growth factors in the pathophysiology of
complications will lead to improved and more specific therapies.

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 PA, The Role of Growth Factors in
the Development of Diabetes Complications, is related to the priority area of
diabetes and chronic disabling conditions. 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 PA will use the National Institutes of Health (NIH) research project
grant (R01) and 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).

This PA will use the modular grants application and award process.  Specific
application instructions have been modified to reflect "MODULAR GRANT" and
"JUST-IN-TIME" streamlining efforts being examined by the NIH.  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. 
Refer to instructions under APPLICATION PROCEDURES, below.  Complete and
detailed instructions and information on Modular Grants can be found at
http://grants.nih.gov/grants/funding/modular/modular.htm

Responsibility for the planning, direction, and execution of the proposed
project will be solely that of the applicant.

FUNDS AVAILABLE

$2 million per year will be set aside by the NIDDK to fund applications
relevant to this PA.  NEI, NIDCR, NINDS, and NHLBI are interested in
applications relevant to this topic but have not set aside specific funds. 
Funding is dependent on the receipt of a sufficient number of applications of
high scientific merit and on the availability of funds for this purpose.

This PA will remain active for three years, through the receipt date of
October 1, 2002.

RESEARCH OBJECTIVES

Background

The micro- and macrovascular complications of diabetes are a major public
health concern.  Diabetic retinopathy is the predominant cause of blindness in
adults, and diabetic nephropathy is a leading cause of end-stage renal
disease. Diabetes is the most common reason for non-traumatic lower extremity
amputations and over 50% of patients with diabetes experience some degree of
neuropathy.  Diabetes results in a greater incidence and severity of
periodontal diseases and other oral mucosal infections, and these infections
can make it harder to control blood glucose levels.  Finally, accelerated
cardiovascular disease remains the major cause of mortality in patients with
diabetes.

The pathologic findings seen in diabetic microvascular complications, as well
as in atherosclerosis, implicate growth factors in their development.  For
example, endothelial proliferation in the eye results in abnormal
neovascularization of the retina. In the kidney, accumulation of mesangial
matrix is the hallmark of diabetic nephropathy.  Atherosclerotic lesions are
also known to involve the accumulation of extracellular matrix, as well as
proliferation of smooth muscle cells.

Studies strongly suggest a role for vascular endothelial growth factor (VEGF)
in the pathogenesis of diabetic proliferative retinopathy. VEGF levels are
increased in the vitreous of animals and humans with diabetic retinopathy, 
and agents which antagonize VEGF will suppress neovascularization of the
retina.  Although the available data indicate that VEGF is likely to play a
critical role in the pathogenesis of diabetic retinopathy, its exact mechanism
at the molecular level is not understood.  Studies are needed to understand
not only the cascade of events triggered by VEGF, but how hyperglycemia leads
to VEGF upregulation.

In the kidney, transforming growth factor (TGF)-beta appears to contribute to
the basement membrane thickening characteristic of diabetic nephropathy.  TGF-
beta levels are elevated in the early stages of nephropathy and inhibition of
TGF-beta appears to prevent glucose-induced stimulation of extracellular
matrix synthesis in vitro.  Levels of other growth factors, including insulin-
like growth factor 1 (IGF-1), fibroblast growth factor (FGF), epidermal growth
factor (EGF), and platelet-derived growth factor (PDGF), are also altered;
however, the role of these other growth factors in the pathogenesis of
diabetic retinopathy and nephropathy is less well characterized than for VEGF
and TGF-beta.  Altered cytokine (e.g., tumor necrosis factor) expression may
also contribute to endothelial dysfunction in diabetes.

Many growth factors and cytokines, including EGF, TGF-beta, TNF-alpha and IGF-
1, require interaction with matrix-associated proteases for release as soluble
proteins that can interact with and activate receptors.  Perturbations in this
critical processing step have been implicated in a variety of
neurodegenerative and inflammatory disorders.  Angiotension converting enzyme
(ACE) is also processed to its active form by matrix proteases.  ACE
inhibitors are used extensively in patients with diabetes to reduce
proteinuria and prevent the progression of diabetic nephropathy, although
their exact renal-protective mechanism of action remains poorly understood.

High levels of gingival crevicular prostaglandins (PGE2) and cytokines (TNF-
alpha, IL-1 beta) are found in type 1 diabetic patients with periodontitis. 
Excess monocytic pro- and anti-inflammatory factors may lead to abnormal wound
healing, tissue destruction and chronic infection in the oral mucosal tissues. 
In addition, high levels of extracellular glucose induce the over-expression
of fibronectin receptors on periodontal ligament cells, suppressing their
ability to migrate in a normal fashion to PDGF.  Such abnormal movement of the
ligament cells could exacerbate the severity and duration of the periodontal
lesion.

Growth factor deficiency, rather than upregulation, is thought to play a role
in the pathogenesis of diabetic neuropathy.  Studies have demonstrated reduced
levels of nerve growth factor (NGF) and IGF-1 in animals and humans with
diabetic neuropathy; however, no direct connection has been made between
reduced levels of neurotrophic factors and the development of diabetic
neuropathy.  In addition, there are multiple members of the nerve growth
factor family, each of which is specifically trophic for a different neuronal
population.  Studies are needed to examine not only tissue-specific but cell-
specific expression of growth factors.

Despite much suggestive evidence implicating growth factors in the development
of the complications of diabetes, much remains to be determined about their
role in the pathophysiology of these disorders.  Little is known about how
multiple growth factors might interact with each other in a specific tissue;
nor is it known how growth factors interface with other abnormalities that
have been implicated in the etiology of complications, including altered
metabolism of polyols, accumulation of advanced glycation end products,
activation of protein kinase C or increased reactive oxygen species.

Finally, study of the pathophysiology of diabetic complications in humans is
often limited by the inability to sample tissues and by the long time that it
takes for complications to develop.  There is clearly a need for the
development of good animal models of diabetic complications, as well as of
surrogate markers that would be useful for monitoring the development and
progression of complications. The use of such markers would also facilitate
the study of potential pharmacologic agents that could be developed, based on
a better understanding of the etiology and pathogenesis of these
complications.

Objectives and Scope

New technologies, including the use of genetic knockouts, transgenic animals
and chip array technology, provide powerful tools for studying the expression
of growth factors during the development of the micro- and macrovascular
complications of diabetes, and for determining the molecular basis for their
actions.  Appropriate topics for investigation would include, but are not
limited to:

o  Studies to evaluate the tissue and/or cell specific expression of various
growth factors during the development of complications, including a temporal
analysis.

o  Studies to determine if activation or release of growth factors by matrix
proteases is altered in diabetes.

o  Studies to determine what genes are up- or down-regulated by altered growth
factor expression.

o  Studies to determine if growth factor signaling pathways are altered in
diabetic complications.

o  Studies to determine how hyperglycemia alters growth factor expression or
action.

o  Studies to determine how other metabolic abnormalities associated with
complications interact with alterations in growth factor expression and/or
action.

o  Studies to test the role of growth factors in the pathogenesis of diabetic
complications using animal models (including the use of knockout or transgenic
animals).

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 new 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.

APPLICATION PROCEDURES

Applications are to be submitted on the grant application form PHS 398 (rev.
4/98) 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, or 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.

Applicants planning to submit an investigator-initiated new (type 1) competing
continuation (type 2), competing supplement, or any amended/revised version of
the preceding grant application types requesting $500,000 or more in direct
costs for any year are advised that he or she must contact NIH program staff
before submitting the application, i.e., as plans for the study are being
developed. Furthermore, the application must obtain agreement from the staff
that the NIH will accept the application for consideration for award. Finally,
the applicant must identify, in a cover letter sent with the application, the
staff member and Institute or Center who agreed to accept assignment of the
application.  This policy requires an applicant to obtain agreement for
acceptance of both any such application and any such subsequent amendment.
Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at
http://grants.nih.gov/grants/guide/notice-files/not98-030.html

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.

Submit the signed, original, single-sided application, including the
Checklist, along with five signed photocopies and five collated sets of
appendix materials 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)

The Center for Scientific Review (CSR) will not accept any application in
response to this PA 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 already reviewed, but such applications must include
an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Applications will be assigned on the basis of established NIH referral
guidelines.  Applications will be evaluated for scientific and technical merit
by an appropriate scientific review group convened in accordance with the
standard 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, generally
the top half of applications under review, will be discussed, assigned a
priority score, and receive a second-level review by the appropriate national
advisory council or board.

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.

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 method?
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?

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.

The initial review group will also examine the provisions for the protection
of human 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 U.S. resources.

AWARD CRITERIA

The following will be considered in making funding decisions:

o  Quality of the proposed project as determined by peer review;
o  Availability of funds;
o  Program priority.

INQUIRIES

Inquiries are encouraged. The opportunity to clarify any issues or questions
from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Barbara Linder, M.D., Ph.D.
Division of Diabetes, Endocrinology and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 5AN18A, MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-0021
FAX:  (301) 480-3503
Email:  linderb@extra.niddk.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.hin.gov

Dennis Mangan, Ph.D.
Division of Extramural Research
National Institute of Dental and Craniofacial Research
45 Center Drive, Room 4AN-32E, MSC 6402
Bethesda, MD 20892-6402
Telephone:  (301) 594-2421
FAX:  (301) 480-8318
Email:  Dennis.Mangan@nih.gov

Paul L. Nichols, Ph.D.
National Institute of Neurological Disorders and Stroke
Neurosciences Center, Room 2118
Bethesda, MD 20892
Telephone:  (301) 496-9964
FAX: (301) 401-2060
Email: pn13w@nih.gov

Dr. Thomas Blaszkowski
Division of Epidemiology and Clinical Applications
National Heart, Lung, and Blood Institute
Rockledge 2, Room 8106, MSC 7938
Bethesda, MD  20892-7938
Telephone:  (301) 435-0417
FAX:  (301) 480-1864
Email:  tb33i@nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Florence Danshes
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-8861

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

Martin Rubinstein
Division of Extramural Research
National Institute of Dental and Craniofacial 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
Neuroscience Center, Room 3254
Bethesda, MD 20892
Telephone:  (301) 496-9231
FAX: (301) 402-0129
Email:  da8h@nih.gov

Ms. Jane R. Davis
Grants Management Office
National Heart, Lung, and Blood Institute
6702 Rockledge Drive, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0165
FAX:  (301) 480-3310
Email:  jane_davis@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.847, 93.867, 93.121, 93.853, 93.837, and 93.854.  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
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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