NON-MOUSE MODELS OF DIABETES COMPLICATIONS IN CARDIOVASCULAR AND MICROVASCULAR 
DISEASES

Release Date:  November 20, 2000

RFA: HL-01-010

National Heart, Lung, and Blood Institute
   http://www.nhlbi.nih.gov/
National Institute of Diabetes and Digestive 
and Kidney Diseases
   http://www.niddk.nih.gov

Letter of Intent Receipt Date: February 26, 2001               
Application Receipt Date: March 21, 2001

PURPOSE

The purpose of this solicitation is to support efforts to develop non-mouse 
animal models of diabetic complications. The animal models are expected to 
mimic vascular diseases in patients with type 1 or type 2 diabetes mellitus 
with an emphasis on, but not limited to, cardiovascular disorders of coronary 
heart disease, stroke, peripheral arterial disease, cardiomyopathy, and 
congestive heart failure.  Improved animal models of microvascular 
complications are also needed. The goal of this initiative is to obtain these 
non-mouse animal models, through the use of selective breeding, dietary 
manipulation, or molecular genetic approaches.  Applicants to this initiative 
are also expected to characterize and validate the models for use in various 
aspects of basic, developmental, or translational research including testing 
prevention, early detection, therapeutic, or diagnostic imaging strategies.  
Applicants should also propose plans to make these models available to other 
research investigators for studies to advance our understanding of the 
etiology, pathobiology, clinical progression, management and prevention of 
diabetic vascular diseases.

A companion RFA (DK-01-009, Mouse Models of Diabetic Complications: 
Consortium) solicits applications to develop mouse models of diabetic 
complications in order to take advantage of unique genetic technologies that 
are applicable in the mouse.

HEALTHY PEOPLE 2010

The Public Health Service (PHS) is committed to achieving the health promotion 
and disease prevention objectives of Healthy People 2010", a PHS-led national 
activity for setting priority areas.  This Request for Applications (RFA), 
Non-Mouse Models Of Diabetes Complications In Cardiovascular And Microvascular 
Diseases, is related to the priority areas, "Heart Disease and Stroke", and 
"Chronic Disabling Conditions".  Potential applicants may obtain a copy of 
AHealthy People 2010" at http://www.health.gov/healthypeople/.

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 or 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.

All current policies and requirements that govern the research grant programs 
of the NIH will apply to grants awarded under this RFA.  Awards under this RFA 
to foreign institutions will be made only for research of very unusual merit, 
need, and promise, and in accordance with Public Health Service policy 
governing such awards. Cell biology, molecular biology, nutrition, 
biochemistry, physiology, pathology, genetics, and imaging modalities are 
among the disciplines and expertise that may be appropriate for this research 
program. 

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) research project 
grant (R01) award mechanism.  Responsibility for the planning, direction, and 
execution of the proposed project will be solely that of the applicant.  The 
total project period for an application submitted in response to this RFA may 
not exceed 5 years.  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.  The anticipated award date is September 30, 2001.

FUNDS AVAILABLE

The NHLBI and NIDDK intend to commit approximately $1,500,000 in FY 2001 to 
fund three to five new grants in response to this RFA. An applicant may 
request a project period of up to five years and a budget for direct costs of 
up to $350,000 per year.  The Facilities and Administrative costs for 
collaborating institutions are excluded from this ceiling and a maximum 
increase of no more than three percent is allowed in each additional year 
requested in the application.   Because the nature and scope of the research 
proposed may vary, it is anticipated that the size of each award will also 
vary.  Although the financial plans of both Institutes provide support for 
this program, awards pursuant to this RFA are contingent upon the availability 
of funds and the receipt of a sufficient number of meritorious applications. 
At this time, it is not known if this RFA will be reissued.

Equipment is included in the budget limitation.  However, requests for major 
equipment that cause an application to exceed this limit may be permitted on a 
case-by-case basis following staff consultation.  Such equipment requires in-
depth justification.  Final decisions will depend on the nature of the 
justification and the Institute's fiscal situation.

Because we expect that there will not be any applications requesting less that 
$250,000 in first year direct costs, applications should be in the standard 
(non-modular) format with a detailed budget.

Consortium Arrangements

When a grant application includes research activities that involve 
institutions other than the grantee institution, it is considered a consortium 
effort.  Such activities may be included in a grant application, but it is 
imperative that a consortium application be prepared so that the programmatic, 
fiscal, and administrative considerations are explained fully.  Facilities and 
administrative costs paid as part of a consortium agreement are excluded from 
the limit on the amount of direct costs that can be requested.  The published 
policy governing consortia is available in the business offices of 
institutions that are eligible to receive Federal grants-in-aid. Consult the 
latest published policy governing consortia before developing the application. 

RESEARCH OBJECTIVES

Background

Prevention and treatment of long-term micro- and macro-vascular complications 
remain a critical problem in the management of patients with type 1 or type 2 
diabetes mellitus. In the United States, diabetes is the leading cause of new 
blindness in adults, of new cases of end stage renal disease and of non-
traumatic lower leg amputations. In addition, cardiovascular complications are 
now the leading cause of diabetes-related morbidity and mortality particularly 
among women and the elderly.  In adult patients with diabetes, the risk of 
cardiovascular disease (CVD)is three to five fold greater than in 
nondiabetics; up to three fourths of all deaths among diabetics can be 
directly attributed to accelerated atherosclerosis and CVD.  A number of known 
risk factors for CVD, such as hypertension, central obesity, and dyslipidemia, 
are more common in diabetics than in the general population. However, no more 
than 25% of the excess coronary artery disease (CAD) risk in diabetics can be 
accounted for by known risk factors such as high plasma cholesterol, low 
plasma HDL, high plasma triglycerides, and hypertension, suggesting the 
presence of other factors contributing to the development of CVD in patients 
with diabetes.

The 1998 Diabetes Research Working Group report noted that a lack of good 
animal models has been a major impediment to research on the long-term micro- 
and macrovascular complications of diabetes. Improved animal models are 
critical for understanding the pathogenesis of complications and for testing 
potential new prevention and treatment modalities. Animal models can be used 
to conduct studies at the molecular, cellular and tissue level not feasible in 
humans. Thus, there is an urgent need to derive, thoroughly characterize, and 
validate animal models for their relevance to human biology, and to use these 
models for testing therapeutic, prevention, early detection or diagnostic 
imaging strategies.

Clinical studies have repeatedly shown a strong correlation between 
susceptibility to micro- and macrovascular complications, especially in 
patients with diabetic nephropathy.  Cardiovascular events are much more 
frequent in patients with diabetic nephropathy. In addition, renal artery 
atherosclerosis may contribute to renal disease; likewise, accelerated lower 
extremity arterial disease interacts with neuropathy, resulting in the high 
rate of lower extremity amputations in patients with diabetes. In addition, it 
is becoming increasingly clear that the pathogenesis of microvascular 
complications, as well as of macrovascular disease, includes disordered 
function of endothelial cells.

There is a growing recognition that diabetes may be increasing the risk of CVD 
partly due to its association with a variety of metabolic abnormalities. 
Hyperglycemia, the defining metabolic change in diabetes, may accelerate the 
development of atherosclerosis.  However, the specific contribution of 
hyperglycemia has been difficult to demonstrate in either population studies 
or animal models.  Moreover, hyperglycemia alone is unlikely to play a role in 
the development of atherosclerosis that is seen in individuals with impaired 
glucose tolerance (IGT) who usually
demonstrate only modest postprandial hyperglycemia.  Therefore, it has been 
suggested that, in addition to glucose levels, other factors associated with 
IGT are likely to contribute to the development of atherosclerosis and CVD in 
type 2 diabetes.  

Thus, it is clear that the pathogenesis of diabetes-related CVD, and the 
mechanisms by which known risk factors may enhance atherosclerosis and CAD are 
poorly understood. In addition, factors contributing to type 1 and type 2 
diabetes, such as autoimmune inflammatory and immunological responses, insulin 
resistance and clustering of CVD risk factors need to be better understood.  
Experimental verification of these potential mechanisms has been greatly 
hindered by a lack of appropriate animal models.  Existing animal models of 
diabetes, CVD and atherosclerosis, although providing useful information, have 
suffered from serious problems. 

A separate RFA (DK-01-009) has been issued which focuses on the development of 
mouse models of diabetic complications.  This initiative solicits applications 
to generate animal models in other species. There is a sizable body of work 
that establishes a number of features in other species which are relevant to 
diabetes-associated vascular disease. 

Nonhuman primates fed atherogenic diets have been used to model human 
atherosclerosis for many years.  However, in some instances, as in the 
squirrel monkey, the plasma cholesterol elevation that develops following 
increased dietary cholesterol results from increases in ß-VLDL rather than in 
LDL. Glucose intolerance and insulin resistance do develop spontaneously in 
some nonhuman primates, although the development of diabetes is much more rare 
than in humans. Therefore, diabetes is most often induced artificially which 
has been problematic as the degree of beta cell damage and the need for 
insulin vary greatly. Moreover, maintaining stable hyperglycemia and healthy 
animals is costly and requires intensive monitoring and care.

Pigs have been frequently favored as an animal model because of their close 
cardiovascular and metabolic similarities to humans.  Natural mutations have 
been identified for the development of hypercholesterolemia. These animals 
developed advanced atherosclerotic lesions, morphologically similar to humans, 
that resulted in their deaths. However, no attempts were made to selectively 
breed these animals for diabetic states. Another pig model, the Yucatan 
miniature swine, was developed by genetic selection for altered glucose 
clearance during a glucose tolerance test.  These animals display insulin 
resistance and a diabetic-like state. On a high fat diet, these animals become 
more glucose intolerant and diabetic.  The cardiovascular and metabolic 
abnormalities in this model have yet to be explored. 

There are currently several animal models of insulin resistance induced by 
high fructose diets. Although this approach has been used in dogs and 
hamsters, fructose enriched diets are most frequently used to induce a 
hyperinsulinemic, euglycemic insulin resistant condition in rats. These diets 
also induce enhanced hepatic secretion of VLDL, frequently resulting in 
moderate hypertriglyceridemia. Although all of these animal models have proven 
useful for studies of insulin resistance, they do not develop extensive 
atherosclerosis or CVD.

The New Zealand White rabbit has also been widely used as a model for 
atherosclerosis.  When fed high cholesterol diets, these rabbits develop 
marked hypercholesterolemia and extensive atherosclerosis. However, 
surprisingly, cholesterol fed rabbits made diabetic by alloxan treatment 
developed less atherosclerosis compared to their nondiabetic controls. This 
apparent paradox has not been explained.  Rabbits lacking functional LDL 
receptors (WHHL rabbits) also develop marked hypercholesterolemia and 
extensive aortic lesions. However, the WHHL rabbit has not been used for 
studies of diabetes and atherosclerosis. Given the absence of spontaneously 
diabetic rabbits and the high mortality of alloxan treated rabbits, rabbits 
have not proven as yet to be a useful model of diabetic atherosclerosis.

Another animal model commonly used for atherosclerosis studies is the hamster. 
However, attempts to chemically induce diabetes have produced variable 
results, with some animals showing marked hyperglycemia, weight loss and poor 
survival, while others develop only moderate hyperglycemia and demonstrate 
prolonged survival.  Diabetic hamsters fed standard or cholesterol enriched 
diets showed ultrastructural changes in the aorta consistent with 
atherosclerosis development. However, the extent of atherosclerosis that 
develops in the diabetic hamster model is modest, and more information is 
needed on the changes in lipoprotein levels and composition that occur.

Several different strains of rats have been proposed as models of type 2 
diabetes. These models were the result of naturally occurring mutations in 
laboratory animals and the recognition that some rats are uniquely susceptible 
to develop insulin resistance and diabetes on special diets. Rats homozygous 
for the "fatty"(fa) or "corpulent"(cp) genes are typically obese, 
hyperlipidemic, hyperinsulinemic and insulin resistant. The "fatty" (Zucker) 
rat has been used primarily as a model of obesity. However, because of the 
accompanying hyperglycemia and insulin resistance it is also useful as a model 
of type 2 diabetes. As in most animal models of insulin resistance, there is 
no evidence of advanced arterial lesion formation in the Zucker rat model.

The corpulent (JCR:LA-cp) rat has marked hyperinsulinemia that develops 
shortly after birth and persists throughout life.  This strain develops 
spontaneous arterial lesions that resemble fatty streaks in humans. However, 
these fatty streaks do not progress to fully developed atherosclerotic 
lesions. This suggests that different etiologies for lesion formation may 
exist in humans and the JCR:LA-cp rat.

Another rat model of type 2 diabetes and atherosclerosis is the sand rat. When 
fed standard rat chow, the sand rat becomes obese, hyperglycemic, 
hyperinsulinemic and insulin resistant.  When made hypothyroid and fed a 
cholesterol-enriched diet, they develop cardiovascular lesions.  However, it 
remains unknown whether factors other than lipid levels contribute to the 
development of atherosclerosis in this strain.

Models of type I diabetes are usually generated by administration of chemicals 
toxic to the pancreas; these animals require insulin to avoid developing 
marked hyperglycemia, dehydration and ketosis. Using low doses of insulin to 
avoid wasting and death while maintaining hyperglycemia to induce 
complications is difficult and time consuming. Therefore, mortality rates are 
frequently high and the possibility that poor health may influence metabolic 
parameters and development of atherosclerosis always remains a concern. As 
noted above, a common limitation of many of the existing animal models of 
diabetes is that they develop only very modest atherosclerosis. Some species, 
particularly the rat and the dog are naturally resistant to developing 
atherosclerosis. In addition, lipoprotein patterns and metabolism in some 
animal models are sufficiently different from those in humans to raise 
concerns about the relevance of risk factors identified in studies using these 
animal models.

To date, available animal models of microvascular complications have also 
shared these limitations. Most of these models have not been fully validated, 
or they reproduce only a small portion of the full human disease. For example, 
there are several rodent models of diabetes associated with renal damage. 
However, these animals generally lack a number of the key pathological 
features seen in human disease. Thus, no animal model consistently exhibits 
the vascular abnormalities, basement membrane thickening and nodule formation 
characteristic of human diabetic nephropathy.

Objectives

The objective of this initiative is to accelerate the pace at which accurate 
and reproducible non-mouse animal models of diabetic vascular complications 
are developed. The animal models are expected to mimic disease in patients 
with type 1 or type 2 diabetes mellitus. The major focus of this RFA is on 
diabetes-associated cardiovascular disorders, including coronary heart 
disease, stroke, peripheral arterial disease, cardiomyopathy, and congestive 
heart failure. However, animals models of microvascular disease are also 
acceptable. The goal of the program is to obtain these non-mouse animal 
models, through selective breeding, dietary or molecular genetic approaches. 
Once the models are developed, characterized and validated, it will be 
important to disseminate the models and information related to them to the 
research community, for studies to advance our understanding of the etiology, 
pathobiology, clinical progression, management and prevention of diabetes 
related cardiovascular and microvascular diseases.  Specific areas of interest 
would include identification of 1) genes which confer protection or induce 
initiation and progression of diabetic vascular disease, 2) environmental 
components that contribute to disease progression and 3) new therapeutic 
strategies to block or retard progression of vascular disease.

It is hoped that rapid progress in creating animal models will be stimulated 
by attracting investigators to integrate approaches involving animal breeding 
and nutrition, vascular physiology, tissue-specific pathology, vascular cell 
biology, molecular analysis of gene expression, clinical investigations, and 
genetics.  More careful characterization and creative utilization of tissue 
and animal resources would expedite this effort.  In addition, cross-breeding 
experiments to explore the interactions of specific genes with various genetic 
backgrounds could be useful. 

Proposed Research

Appropriate investigations under this RFA would include, but not be limited 
to, the generation and characterization of non-mouse animal model(s) of 
insulin resistance or diabetes, which develop vascular disease which resembles 
that seen in humans with type 1 or type 2 diabetes.  Applicants must also 
outline their proposed plans to make these animals available to the research 
community.

It is envisaged that the most appropriate animal models of type I diabetes 
would have low insulin levels, while models of type 2 diabetes would have 
normal or slightly elevated plasma insulin. The models should also have 
moderate to severe hyperglycemia and lipoprotein patterns typical of those 
present in human diabetes. Atherosclerotic lesions in these models should have 
many of the morphologic and cellular features characteristic of early and 
advanced human lesions. Finally, the models should fulfill several practical 
criteria for in vivo studies of atherosclerosis such as development of 
atherosclerotic lesions and/or kidney dysfunction within a relatively short 
time to allow the detection of differences between experimental and control 
groups.  Similarly, new models of diabetic microvascular disease must 
demonstrate pathology analogous to human disease.

EXCLUSIONS

This RFA is intended to support R01 research programs to create, characterize, 
evaluate, and disseminate non-mouse animal models to study diabetes 
complications of accelerated atherosclerosis, and other cardiovascular 
diseases, as well as microvascular disease cardiovascular and kidney diseases. 
Applications that propose mouse models will be considered unresponsive to this 
initiative.  Investigators proposing mouse models may wish to consider RFA : 
DK -01-009 entitled "Mouse Models of Diabetic Complications Consortium" or 
consult with the NHLBI and NIDDK staff at the address listed under INQUIRIES. 

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI and the NIDDK will sponsor periodic 
meetings to encourage exchange of information among investigators who 
participate in this program.  Applicants should request travel funds for a 1 
day meeting each year, most likely to be held in Bethesda, Maryland.  
Applicants should include a statement in their applications indicating their 
willingness to participate in these meetings.

URLS IN NIH GRANT APPLICATIONS OR APPENDICES

All applications and proposals for NIH funding must be self-contained within 
specified page limitations. Unless otherwise specified in an NIH solicitation, 
internet addresses (URLs) should not be used to provide information necessary 
to the review because reviewers are under no obligation to view the Internet 
sites. Reviewers are cautioned that their anonymity may be compromised when 
they directly access an Internet site.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 26, 2001 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 the RFA in response to which the application may be submitted.  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 
staff to estimate the potential review workload and to plan the review.

The letter of intent is to be mailed, or faxed, to: Dr. Deborah Beebe at the 
address listed under INQUIRIES.

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in 
applying for these grants, with the modifications noted below.  These forms 
are available at most institutional offices of sponsored research, and 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. 

Because we expect that there will not be any applications requesting less that 
$250,000 in first year direct costs, applications should be in the standard 
(non-modular) format with a detailed budget.

The RFA label found in the PHS 398 (rev. 4/98) 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 
(Non-Mouse Models of Diabetes Complications in Cardiovascular and Kidney 
Diseases) and number (HL -01-010) must be typed on line 2 of the face page of 
the application form and the YES box must be marked.

The sample RFA label available at: email: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf  
has been modified to allow for this change. Please note this is in pdf format.

Submit a signed typewritten original of the application and 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 the time of submission, two additional copies of the application must be 
sent to Dr. Deborah Beebe, Chief, Review Branch at the address listed under 
INQUIRIES.  It is important to send these two copies at the same time as the 
original and three copies are sent to the Center for Scientific Review (CSR), 
otherwise the NHLBI cannot guarantee that the application will be reviewed in 
competition for this RFA.

Applications must be received by March 21, 2001. 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 already reviewed, but such applications must include 
an introduction addressing the previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the CSR, and 
responsiveness by NHLBI and NIDDK.  Incomplete and/or non-responsive 
applications will be returned to the applicant without further consideration. 
 
Applications that are complete and responsive to the RFA will be evaluated for 
scientific and technical merit by an appropriate peer review group convened by 
the NHLBI in accordance with the review criteria stated below. 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 the applications under review, 
will be discussed, assigned a priority score, and receive a second level 
review by the advisory councils of NHLBI and NIDDK.

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 reviewers 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.

1) 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?

2) 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?  Once the models are developed, characterized and validated, does the 
applicant propose plans for the efficient dissemination of the models and 
information related to them to the research community?

3) 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?

4) 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 an)?

5) 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 The reasonableness of the proposed budget and duration in relation to the 
proposed research. 
o The adequacy of the proposed protection for animals or the environment, to 
the extent they may be adversely affected by the project proposed in the 
application.
o The adequacy of the proposed plan to share and disseminate the animal 
models.

SCHEDULE

Letter of Intent Receipt Date:      February 26, 2001
Application Receipt Date:           March 21, 2001
Review by NHLBI Advisory Council:   September 6-7, 2001
Anticipated Award Date:             September 30, 2001

AWARD CRITERIA

Applications will receive a secondary level of review by advisory councils of 
NHLBI and NIDDK in September, 2001.  The earliest anticipated date of award is 
September 2001. Applicants should be aware that, in addition to scientific 
merit, program priorities and program balance, the total costs of the proposed 
project and the availability of funds will be considered by NHLBI staff as 
well as NHLBAC in making funding recommendations.  In addition, NHLBI 
appreciates the value of complementary funding from other public and private 
sources including foundations and industrial concerns.  In circumstances in 
which applications have similar scientific merit, but vary in cost 
competitiveness, NHLBI is likely to select the more cost competitive 
application for funding.

INQUIRIES

Inquiries concerning this RFA are encouraged.  Potential applicants should 
request a copy of the full RFA, which will include sample budget pages. The 
opportunity to clarify any issues or questions from potential applicants is 
welcome.

Direct inquiries regarding programmatic issues to:

Momtaz Wassef, Ph.D.
Leader, Atherosclerosis Research Group
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10186
Bethesda, MD  20892-7956
Telephone:  (301) 435-0550 
FAX:  (301) 480-2848
E-mail: WASSEFM@NIH.GOV

Barbara Linder, M.D.
Division of Diabetes, Endocrinology 
and Metabolic Diseases
National Institute of Diabetes and Digestive
and Kidney Diseases
6707 Democracy Blvd
Bethesda, MD 20892-5460
Telephone: (301) 594-0021  
Fax: (301) 480-3503
E-mail: LINDERB@NIH.GOV 

Direct inquiries regarding review issues, send letter of intent and two copies 
of the application to:

Dr. Deborah Beebe
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7178, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301)435-0270
FAX: (301) 480-3541
E-mail: Beebeb@NIH.GOV  

Direct inquiries regarding fiscal matters to:

Mr. Owen Bobbitt
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 7156
Bethesda, MD  20892-7926
Telephone:  (301)435-0177, FAX:  (301)480-3310
E-mail: BobbittO@NIH.GOV  

AUTHORITY AND REGULATIONS

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