THE ROLE OF ENDOTHELIAL DYSFUNCTION IN DIABETIC COMPLICATIONS

Release Date:  December 13, 1999

PA NUMBER:  PA-00-026

National Institute of Diabetes and Digestive and Kidney Diseases

THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  IT INCLUDES 
DETAILED MODIFICATIONS TO 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) 
invites investigator-initiated research grant applications to study the role 
of endothelial alteration or dysfunction in the etiology and pathogenesis of 
the micro- and macrovascular complications of diabetes.  Endothelial function 
is known to be abnormal in diabetes and may be an early step in the 
development of atherosclerotic lesions.  Recent work has also focused 
attention on the role of endothelial function in the pathogenesis of 
microvascular complications.  This PA, with a $1 million dollar annual set-
aside, is intended to stimulate the application of new molecular technologies 
to this area.  Understanding the pathogenesis of endothelial dysfunction in 
diabetes at the molecular and cellular level will provide new targets for 
pharmacologic or genetic manipulations to prevent complications of diabetes.

HEALTHY PEOPLE 2000

The Department of Health and Human Services (DHHS) is committed to achieving 
the health promotion and disease prevention objectives of "Healthy People 
2000," a DHHS-led national activity for setting priority areas.  This PA, The 
Role of Endothelial Dysfunction in Diabetic 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.  Responsibility for the planning, direction, and execution of the 
proposed project will be solely that of the applicant.  The total project 
period for an R01 application submitted in response to this PA may not exceed 
5 years.

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.

Specific application instructions have been modified to reflect "MODULAR 
GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH.  
Complete and detailed instructions and information on Modular Grants can be 
found at http://grants.nih.gov/grants/funding/modular/modular.htm

FUNDS AVAILABLE

$1 million will be set aside by NIDDK in FY 2001, 2002, and 2003 to fund 
competing applications relevant to this PA.  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.

RESEARCH OBJECTIVES

Background

Diabetes is the leading cause of end stage renal disease, blindness in 
adults, and non-traumatic lower leg amputations.  In addition, individuals 
with diabetes have a 2- to 4-fold increased risk of developing, and dying 
from, cardiovascular disease.  One in ten health care dollars in the United 
States is spent on diabetes; most of these health care costs are incurred in 
the treatment of macro- and microvascular complications. 

Endothelial dysfunction is a key feature of diabetes and is thought to be a 
major cause of the associated vascular complications.  Endothelial cell 
damage, with loss of the vascular protective effects of nitric oxide (NO), is 
a likely early step in the accelerated atherosclerosis of diabetes.  Impaired 
endothelial-dependent vasodilatation has been described in patients with type 
1 and type 2 diabetes, and the degree of impairment may correlate with 
glycemic control.  Hyperglycemia itself appears to affect multiple mechanisms 
that increase atherosclerosis. Hyperglycemia enhances oxidation, thrombosis, 
inflammation, matrix production, and the formation of advanced glycation end 
products and other metabolites that can potentially damage the vasculature.  
Insulin may also play an important role in atherogenesis.  Even in the 
absence of diabetes, patients with insulin resistance are at significantly 
increased risk for atherosclerosis. Insulin resistance is associated with 
hypertriglyceridemia and a preponderance of small, dense low density 
lipoprotein (LDL).  This LDL phenotype may be more susceptible to oxidative 
modification, a process that promotes atherosclerosis by impairing 
endothelial cell function, stimulating inflammation and adhesion, and 
promoting vascular smooth muscle cell changes.  Insulin itself stimulates 
vascular smooth muscle cell migration, growth and matrix production, and 
enhances clot formation.  Insulin resistance is also associated with impaired 
NO production.

Endothelial dysfunction may also contribute substantially to the pathogenesis 
of microvascular complications. Diabetic nephropathy results from changes in 
blood flow in small vessels with an increase in mesangial cells and excess 
accumulation of extracellular matrix.  The earliest retinal abnormalities 
induced by hyperglycemia are impaired autoregulation of retinal blood flow 
and decreased retinal blood flow, associated with loss of endothelial-
supporting pericytes from retinal capillaries.  These changes are followed by 
endothelial cell permeability changes and retinal capillary occlusion.  In 
diabetic peripheral sensory neuropathy, capillary closure is frequently 
observed in the vasa nervorum, and endoneurial blood flow and oxygen tension 
are reduced.

The molecular basis of endothelial cell dysfunction in diabetes is not well 
understood.  Mechanisms by which hyperglycemia may cause microvascular damage 
include: increased polyol pathway activity and associated changes in 
intracellular redox state, increased diacylglycerol synthesis with consequent 
activation of protein kinase C, increased nonenzymatic glycation of both 
intracellular and extracellular proteins, and increased formation of reactive 
oxygen species.  Increased free radical generation, increased oxidative 
stress and abnormal plasma lipid composition have all been implicated in 
macrovascular endothelial cell dysfunction.

Determining the effects of hyperglycemia on endothelial function and the 
subsequent role of endothelial abnormalities in the development of diabetic 
vascular lesions is critical to understanding the etiology and pathogenesis 
of the micro- and macrovascular complications of diabetes.  Dissecting these 
pathways will provide new targets for effective therapeutic or prevention 
strategies.

Objectives and Scope

Recent advances in understanding endothelial cell biology, coupled with new 
molecular technologies, provide powerful tools for studying endothelial 
function in diabetes.  In addition, 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 diabetic 
complications.  Appropriate topics for investigation would include, but are 
not limited to:

o Studies to determine how hyperglycemia alters endothelial and/or vascular 
smooth muscle cell function, including changes in gene expression.

o Studies to determine what genes modulate susceptibility of tissues to 
hyperglycemia-induced injury.

o Studies to understand the sequence of events in the pathogenesis of 
hyperglycemia-induced vascular injury.

o Studies to determine how vascular inflammation is altered in diabetes.

o Studies to determine the effects of insulin in vascular cells at the 
molecular and physiologic levels.

o Studies to determine how specific alterations in circulating lipids in 
patients with diabetes affect the development and expansion of 
atherosclerotic lesions.

o Studies to determine how hyperglycemia or hyperinsulinemia alter hemostasis 
and cellular interactions at the surface of unstable atherosclerotic plaques.

o Studies to evaluate how antidiabetic drugs affect the vasculature and the 
coagulation system, and determine what impact they may have on 
atherosclerosis development and progression. 

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 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, 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 the 
NIDDK program staff before submitting the application, i.e., as plans for the 
study are being developed.  Furthermore, the applicant must obtain agreement 
from the staff that the NIDDK 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.

The goal of this PA is to stimulate investigations of endothelial alteration 
or dysfunction in the etiology and pathogenesis of the complications of 
diabetes. Applications that deal primarily with the macrovascular 
complications of diabetes may also be assigned to the National Heart, Lung 
and Blood Institute based on current CSR referral guidelines.

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.

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

Applications will compete for available funds with all other recommended 
applications.  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
NIDDK
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-0021
FAX:  (301) 480-3503
E-mail:  linderb@extra.niddk.nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Florence Danshes
Division of Extramural Activities
NIDDK
45 Center Drive MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-8861

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No. 
93.847. 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 NIH grants policies and Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92.  This program is not 
subject to the intergovernmental review requirements of Executive Order 12372 
or Health Systems Agency review.

The NIH 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 NIH mission to protect and advance the physical and mental health of 
the American people.

Return to Volume Index

Return to NIH Guide Main Index

	Office of Extramural Research (OER)			National Institutes of Health (NIH) 9000 Rockville Pike Bethesda, Maryland 20892			Department of Health and Human Services (HHS)
Note: For help accessing PDF, RTF, MS Word, Excel, PowerPoint, RealPlayer, Video or Flash files, see Help Downloading Files.