PATHOPHYSIOLOGIC MECHANISMS OF OBESITY-ASSOCIATED CARDIOVASCULAR DISEASE
 
RELEASE DATE:  January 25, 2002
 
RFA:  RFA-HL-02-016

PARTICIPATING INSTITUTES AND CENTERS (ICs):
 
National Heart, Lung, and Blood Institute (NHLBI)
 (http://www.nhlbi.nih.gov)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
 (http://www.niddk.nih.gov)

LETTER OF INTENT RECEIPT DATE:  May 20, 2002

APPLICATION RECEIPT DATE:  June 19, 2002
 
THIS RFA CONTAINS THE FOLLOWING INFORMATION

o Purpose of this RFA
o Research Objectives
o Mechanism of Support
o Funds Available
o Eligible Institutions
o Individuals Eligible to Become Principal Investigators
o Special Requirements
o Where to Send Inquiries
o Letter of Intent
o Submitting an Application
o Peer Review Process
o Review Criteria
o Receipt and Review Schedule
o Award Criteria
o Required Federal Citations

PURPOSE OF THIS RFA

The purpose of this Request for Applications (RFA) is to stimulate novel 
research approaches to clarify the biologic basis of various obesity-
related cardiovascular diseases and disorders, including 
atherosclerosis, thrombosis, hypertension, cardiomyopathies, heart 
failure, and arrhythmias/sudden death.  Emphasis will be placed on basic 
and clinical mechanistic research that reflects expertise in both 
obesity and cardiovascular sciences.  Areas of high interest in 
association with cardiovascular disorders include: adipose tissue as a 
pro-inflammatory and pro-thrombotic endocrine organ; lipid infiltration 
(lipotoxicity) in non-adipose tissues and organs; maladaptation of the 
cardiovascular, endocrine, and neural systems in obesity; and the impact 
of obesity on the maturation of the cardiovascular system in young 
animals.  Applications may also include the development of shared 
research resources, provided these are proposed in conjunction with 
hypothesis-testing study designs. 

RESEARCH OBJECTIVES

Background

The adult United States population, whose combined prevalence of 
overweight and obesity now exceeds 60 percent, is experiencing a mass 
exposure to obesity-related cardiovascular risk factors and will likely 
suffer the adverse clinical consequences in years to come.  Overweight 
or obese individuals experience greatly elevated morbidity and mortality 
from nearly all of the common cardiovascular diseases (stroke; coronary 
heart disease; congestive heart failure; cardiomyopathy; and possibly 
arrhythmia/sudden death).  This is partly attributable to co-morbidities 
and risk factors such as type 2 diabetes, insulin resistance, 
hypertension, and dyslipidemias.  The residual independent effects of 
obesity on cardiovascular risk, however, detected in long-term 
prospective studies with decades of observation, suggest a role for less 
well-characterized mediators such as sleep-disordered breathing, 
autonomic dysregulation, and pro-thrombotic and pro-inflammatory states. 
 
Also alarming are the ever rising rates of overweight and obesity in 
children and adolescents, which have tripled over the last 30 years.  
Increased rates of co-morbidities such as type 2 diabetes and hepatic 
damage in overweight adolescents indicate that the young are not 
protected from the metabolic perturbations that accompany excess adipose 
tissue stores.  We do not know what the consequences might be for the 
still-developing cardiovascular system if obesity is present during late 
stages of growth and maturation.

The specific relationships between obesity and cardiovascular risk vary 
considerably with gender, race, and type of heart disease.  For example, 
congestive heart failure risk is similarly elevated in overweight/obese 
males and females.  There is debate, however, regarding whether there 
are gender differences in risk of coronary heart disease at given 
degrees of overweight.  The effect of adiposity on stroke risk, on the 
other hand, appears to vary with race as well as gender.  These varied 
findings suggest that complex underlying phenomena may mediate the 
relationship between excess adipose tissue and elevated cardiovascular 
disease risk.  For example, the biological implications of gender- and 
race-related differences in adipose tissue distribution should be 
explored.  Also, differences in hormone metabolism and hormonal effects 
on cardiovascular biology, including the role of androgens, estrogens, 
and hormone-replacement therapies, need further study.  

Mechanistic Studies in Animals and Humans

Because primary treatment and prevention of obesity often fail or are 
only partially successful, it is anticipated that the future will bring 
ever-increasing demands to treat the cardiovascular conditions 
attributable to obesity.  Thus, in order to develop rational therapeutic 
approaches, we need to understand the basic biology of obesity-related 
cardiovascular disease.  

Adipose tissue as a metabolically active endocrine organ:
While a major role of adipose tissue is the storage of lipid energy, 
recent work has highlighted the role of adipose tissue as a 
metabolically active endocrine organ.  Notably, insights into the 
biology of the secretion of the hormone leptin from adipocytes and its 
action in the central nervous system have contributed to our 
understanding of the regulation of energy balance.  However, leptin=s 
direct effects on the cardiovascular system are only now being revealed. 
For example,  important interactions between adipose tissue and 
coagulation pathways have been suggested by recent reports that platelet 
membranes contain leptin receptors.  Studies also are needed to clarify 
leptin=s effects on sympathetic nervous activity and cardiovascular 
functions such as blood pressure control.  Likewise, more research is 
needed regarding the intriguing connections between leptin physiology 
and sleep physiology suggested by observations that repeated 
interruptions in breathing due to sleep apnea may lead to altered plasma 
leptin levels. 

Other newly discovered molecules of adipose tissue origin, such as 
perilipin, adiponectin, and resistin, are potentially of interest with 
regard to their interactions with the cardivascular system.  Adipocyte-
derived angiotensinogen and angiotensin II are of interest because the 
renin/angiotensin/aldosterone system plays a major role in the 
pathophysiology of hypertension and related sequelae such as cardiac 
hypertrophy, diastolic dysfunction and heart failure.  

The importance of specific metabolic characteristics of various regional 
fat depots has recently been underscored by observations that abdominal 
obesity is associated with the upregulation of 11-beta-hydroxysteroid 
dehydrogenase type 1 in visceral fat.  This may have implications for 
the relationship between this type of obesity and development of the 
metabolic syndrome (Syndrome X).

Lipotoxicity in muscle and other non-adipose tissues:
The deleterious effects of increased infiltration of free fatty acids 
(FFA) into various organs and tissues have been collectively termed 
"lipotoxicity".  The potential importance of this concept was recently 
highlighted by animal studies suggesting that excess fatty acids help 
destroy cardiac myocytes by increasing triglyceride content and the rate 
of apoptosis.  Lipid accumulation in the pancreas and the liver also 
conveys serious functional risks.  Still unclear are the mechanisms for 
the tissue-specific uptake of FFA and their deposition into stored lipid 
pools;  the molecular and pathophysiologic basis for the organ-specific 
toxicity of lipid accumulation; and the relationship of such lipid 
deposition  to development of various cardiovascular diseases.  We also 
need to understand the ways in which the functional effects of 
lipotoxicity in the heart and vascular tissues are distinct from those 
of glucotoxicity.  In addition, more research is needed on the basic 
mechanisms of human lipotoxic heart disease and obesity cardiomyopathy.

Inflammation and thrombosis:
It is now well accepted that inflammation is a major component of 
atherosclerosis.  Moreover, adipose tissue is now recognized as a source 
of inflammatory mediators, with production of cytokines such as TNF-
alpha and interleukin-6.  It appears likely, but is far from proven, 
that the relationship between obesity, insulin resistance, and 
atherosclerosis may depend at least in part on the increased production 
and release of these inflammatory mediators from adipose tissue.  Other 
secretory products of adipose tissue (e.g. angiotensin II) and their 
relationship to inflammation in obesity also need to be investigated.

Obesity is a pro-thrombotic state, possibly as a secondary effect of 
insulin resistance; this is a contributing factor to elevated risk of 
coronary heart disease and stroke.  Pulmonary thromboembolic disease 
also occurs at higher rates in the obese, in part but perhaps not 
entirely due to venous stasis.  For example, the increased flux of FFA 
that occurs in obesity likely promotes thrombosis through alterations in 
protein C, tissue factor PAI-1 and/or enhanced platelet aggregation.  
Enhanced secretion of inflammatory mediators from an expanded adipose 
tissue compartment may also activate thrombotic mechanisms in obesity. 

Hemodynamic and neural/sympathetic regulation:

Many hemodynamic abnormalities have been described in obesity, including 
elevated cardiac output, altered vascular reactivity, hypertension, 
diastolic dysfunction, and cardiomyopathy.  It is not clear whether 
these abnormalities stem from direct effects of adipose tissue excess, 
in addition to well-known secondary or indirect mechanisms.  For 
example, the hemodynamic pathophysiology in obesity apparently derives 
in part from maladaptive neural regulation of the circulation in the 
setting of an expanded adipose tissue mass.  Also, the obstructive sleep 
apnea that frequently occurs in obesity produces abrupt increases in 
sympathetic activity, with altered vascular responses that include 
increased blood pressure, all of which persist even through the waking 
hours; obstructive sleep apnea thus may be an important secondary cause 
of hypertension.  

Both the central and peripheral nervous systems appear to be intricately 
involved in the development of obesity and also in the resulting 
cardiovascular complications.  Sympathetic activation is involved in 
many of the cardiovascular complications of obesity, including 
hypertension, diastolic dysfunction, congestive heart failure, 
obstructive sleep apnea, and cardiac arrhythmias.  The mechanisms for 
this dysregulation and complex, integrated afferent and efferent signals 
are poorly understood.  

In addition, altered renal function and excess sodium reabsorption by 
the kidney play a major role in obesity-induced hemodynamic 
abnormalities.  In experimental animals, caloric excess causes renal 
disease as well as obesity, whereas caloric restriction protects against 
injury to the glomerulus.  However, the mechanisms that link obesity 
with impaired kidney function are poorly understood.  For example, the 
mechanisms that cause progressive nephron loss are unclear.  Few 
clinical or experimental studies have examined the initial changes in 
glomerular structure and function in the early stages of obesity. These 
changes may be the precursors to the development of more severe 
glomerulosclerosis and eventual loss of nephron function, and also be 
markers for more generalized vascular disease. 

The factors that allow risk stratification and those that predict 
pharmacological responsiveness to drugs such as angiotensin converting 
enzyme inhibitors and aldosterone antagonists also need to be understood.

Lipid metabolism, hyperinsulinemia, and atherosclerosis:
The relative roles of various lipid and lipoprotein disturbances in 
subsequent development of coronary heart disease in obesity are still 
not fully understood.  The most common lipid disturbance in obese 
patients is the reduction of plasma high density lipoprotein (HDL) 
cholesterol concentration.  This abnormality in part derives from 
compositional changes in HDL that reflect the hypertriglyceridemic state 
(i.e., replacement of cholesteryl ester by triglycerides), but reduced 
HDL cholesterol levels are often seen in obese patients without 
increases in serum triglycerides.  A more in-depth understanding of the 
origin of low levels of HDL in obesity is ripe for basic and 
translational study. 

Increased progression of atherosclerosis in obesity may also be related 
to increased levels of apoB lipoproteins.  Increased secretion of VLDL-
apoB has been related to increased free fatty acid flux, causing 
decreased intracellular degradation and hence increased secretion. A few 
studies have suggested that insulin resistance at the level of the 
hepatocyte can also lead to increased apoB secretion.  The mechanisms 
linking free fatty acid flux or insulin resistance (at the level of the 
hepatocytes) to increased apoB secretion are incompletely understood and 
deserve further study.  Insulin resistance, apparently a primary 
mechanism of type 2 diabetes, has received little attention as a 
mechanism of increased atherosclerosis risk.

Changes related to hyperglycemia or defective insulin signaling may also 
be involved in the increased atherosclerosis risk associated with 
obesity.  For example, in diabetic humans blood glucose control is not 
well correlated with atherosclerotic cardiovascular disease, in contrast 
to the beneficial effects on microvascular disease.  Also, in murine 
models hyperglycemia has not been clearly shown to increase 
atherosclerosis, independent of plasma lipid changes.  Furthermore, the 
possibility that obesity-related defects in insulin signaling affect the 
behavior of cells in the atherosclerosis-susceptible regions of arteries 
warrants investigation.  A very small number of studies suggest there 
may be pro-atherogenic abnormalities of endothelial cells or macrophages 
that could be related to defects in insulin signaling.

Furthermore, the mechanism by which the hyperinsulinemia of obesity 
contributes to cardiovascular disease is not well understood, and may 
not be simply explained by an association between insulin resistance and 
coexisting factors such as dyslipidemia.  For example, there are recent 
data that indicate the metabolic effects of insulin action are 
biochemically distinct from the mitogenic effects of the hormone.  
Moreover, some models demonstrate that when insulin resistance is 
present in the metabolic pathways of insulin action, the mitogenic 
pathways are not only maintained, but in fact show compensatory 
increases.  This could promote atherogenic events in the arterial wall. 
 
Research Resources

In conjunction with proposed hypothesis-testing research designs, 
applications may also include usage and/or development of various types 
of research resources, which could range from whole animals to 
immortalized cell lines to advanced instrumentation.  Applicants are 
encouraged to describe plans for sharing such resources with 
other investigators.

Animal models:
To examine the cardiovascular pathophysiology of obesity, consideration 
should be given to novel uses of currently available genetic and 
experimental models.  Nevertheless, suitable animal models for examining 
the impact of obesity on cardiovascular disease are relatively limited 
at present, and new ones need to be developed.  For example, large 
animal models (e.g., non-human primates, swine) may be appropriate for 
certain investigations.  Also, immature and growing animals could be 
studied at various stages of the life cycle.  Furthermore, in addition 
to diet-induced and genetically-based animal models of obesity and 
overweight, distinct lean and thin phenotypes may be useful.  

Technology:
Applicants are encouraged to propose research that takes advantage of, 
and further builds upon, recent technology developments.  Complex 
instrumentation for phenotyping could be considered as appropriate.  
Examples include ultrasound, computerized tomography, and magnetic 
resonance imaging techniques to enhance the definition of body and organ 
composition and whole room or chamber calorimeters to assess animal and 
human energy balance.  Mass spectrometric analysis of stable isotope 
turnover may be useful in identifying mechanisms for tissue-specific 
fuel utilization.  The development of methods for high-throughput 
macromolecular identification of tissues and cells and non-invasive 
methods of assessing lipid infiltration into tissues and organs would be 
useful.  DNA and protein microarray analyses could be applied to the 
investigation of tissues from various body compositional phenotypes of 
animals and humans.  

Summary of Priority Areas

Areas of particularly high interest for mechanistic research in humans 
and animals include: 
o  Adipose tissue as a pro-inflammatory, pro-thrombotic endocrine organ 
affecting the cardiovascular system
o  Lipid infiltration as a cause of target organ injury in the 
cardiovascular system
o  CNS adaptation and autonomic activation in obesity, including sleep 
apnea, and their impact on cardiovascular regulation
o  Obesity-associated hypertension and hypertensive renal disease 
o  Cardiovascular adaptations to obesity during various stages of 
development and maturation, from childhood through adolescence
o  Hyperinsulinemia, insulin resistance, and other endocrine 
dysregulation syndromes of obesity as related to cardiovascular disease 

MECHANISM OF SUPPORT
 
This RFA will use the National Institutes of Health (NIH) Individual 
Research Project Grant (R01) award mechanism.  As an applicant you will 
be solely responsible for planning, directing, and executing the 
proposed project.  This RFA is a one-time solicitation.  Future 
unsolicited, competing-continuation applications based on this project 
will compete with all investigator-initiated applications and will be 
reviewed according to the customary peer review procedures. The 
anticipated award date is April 1, 2003.

This RFA uses just-in-time concepts.  It also uses the modular as well 
as the non-modular budgeting formats (see 
http://grants.nih.gov/grants/funding/modular/modular.htm).  
Specifically, if you are submitting an application with direct costs in 
each year of $250,000 or less, use the modular format.  Otherwise follow 
the instructions for non-modular research grant applications.

FUNDS AVAILABLE
 
The NHLBI intends to commit approximately $6,000,000 (Total Cost) and 
the NIDDK intends to commit approximately $1,000,000 (Total Cost) in 
FY2003 to fund approximately 10-12 new grants in response to this RFA. 
An applicant may request a project period not to exceed 5 years and a 
budget for direct costs not to exceed $500,000 per year. Because the 
nature and scope of the proposed research will vary from application to 
application, it is anticipated that the size and duration of each award 
will also vary.  Although the financial plans of the NHLBI and NIDDK 
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.

ELIGIBLE INSTITUTIONS
 
You may submit an application if your institution has any of the 
following characteristics:

o For-profit or non-profit organizations 
o Public or private institutions, such as universities, colleges, 
hospitals, and laboratories 
o Units of State and local governments
o Eligible agencies of the Federal government  
o Domestic or foreign

INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS   

Any individual with the skills, knowledge, and resources necessary to 
carry out the proposed research is invited to work with his or her 
institution to develop an application for support.  Individuals from 
under-represented racial and ethnic groups as well as individuals with 
disabilities are always encouraged to apply for NIH programs.

SPECIAL REQUIREMENTS

Exclusions

Certain types of investigations, although potentially of scientific 
interest, will not be appropriate for support by this program.  
Applications proposing non-mechanistic, non-hypothesis-based research 
will be considered non-responsive to the RFA.  Examples of excluded 
studies are: prospective or descriptive epidemiology studies (e.g., 
investigating health risks of obesity); clinical trials whose primary 
purpose is to test effectiveness of treatments or interventions for 
obesity or associated cardiovascular diseases; studies having a primary 
focus on causation of obesity or on mechanisms of energy balance; 
studies having a primary focus on cardiovascular conditions, but which 
do not include the biology of obesity or overweight as an aspect of the 
experimental design; and projects having a primary focus on research 
resource development.

Grantees= Meetings

Upon initiation of the program, the NHLBI and NIDDK will sponsor annual 
meetings to encourage exchange of information among investigators who 
participate in this program.  In their budgets, applicants should 
include funds for annual one-day grantees= meetings, most likely in 
Bethesda, Maryland.  Applicants should also include a statement in their 
applications indicating their willingness to participate in these 
meetings. The first such meeting likely will take place within 3 months 
of award. 

General Clinical Research Center (GCRC)

Applicants from institutions that have a GCRC funded by the NIH National 
Center for Research Resources may wish to identify the GCRC as a 
resource for conducting the proposed research.  If so, a letter of 
agreement from either the GCRC program director or principal 
investigator should be included with the application.

Additional Considerations

All grant applications submitted in response to this RFA should include 
sample size and statistical power calculations appropriate to the 
proposed study design.  In addition, applicants proposing development of 
research resources are encouraged to describe a plan to share such 
resources with other researchers.   This could include appropriate 
information technology (such as DNA/protein microarray databases) or 
shipment of animals or tissues. 

WHERE TO SEND INQUIRIES

We encourage inquiries concerning this RFA and welcome the opportunity 
to answer questions from potential applicants.  

It is particularly recommended that prospective applicants make these 
inquiries, especially regarding scientific/research issues, as soon as 
possible, i.e., considerably in advance of submitting the Letter of 
Intent.  Doing so will allow a preliminary evaluation of responsiveness 
to be made at an early stage and will help to prevent the preparation 
and/or submission of an unresponsive application. 

Inquiries may fall into three areas:  scientific/research, peer review, 
and financial or grants management issues:

o Direct your questions about scientific/research issues to:

Abby G. Ershow, Sc.D. 
Division of Heart and Vascular Diseases 
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Suite 10193,  MSC 7956
Bethesda, MD  20892-7956
Telephone:  (301) 435-0550 or 435-0526
Fax:  (301) 480-2858
Email:  ErshowA@nhlbi.nih.gov

Carl E. Hunt, M.D.
Director, National Center on Sleep Disorders Research
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Suite 10038 MSC 7920
Bethesda, MD  20892-7920
Telephone:  (301) 435-0199
Fax:  (301) 480-3451
Email:  HuntC@nhlbi.nih.gov

Susan Z. Yanovski, M.D.
Director, Obesity and Eating Disorders Program
Division of Digestive Diseases and Nutrition
National Institute of Diabetes and Digestive and Kidney Diseases
6707 Democracy Boulevard, MSC 5450
Bethesda, MD  20892-5450
Telephone:  (301) 594-8882
Fax:  (301) 480-8300
Email:  sy29f@nih.gov

o Direct your questions about peer review issues, letters of intent, and 
application procedures to:

Anne Clark, Ph.D.
Chief, Review Branch
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) 480-0730
Email:  ClarkA@nhlbi.nih.gov

o Direct your questions about financial or grants management matters to:

David Reiter
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive
Suite 7159, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0153
FAX:  (301) 480-3310
Email:  ReiterD@nhlbi.nih.gov

LETTER OF INTENT

Prospective applicants are asked to submit a letter of intent that 
includes the following information:

o Descriptive title of the proposed research
o Name, address, and telephone number of the Principal Investigator
o Names of other key personnel 
o Participating institutions
o Number and title of this RFA 

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 NHLBI staff to estimate the potential review 
workload and plan the review.  Such letters also are helpful to staff in 
making a preliminary assessment of responsiveness to the RFA.  

The letter of intent is to be sent by May 20, 2002 to:

Anne Clark, Ph.D.
Chief, Review Branch
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) 480-0730
Email:  ClarkA@nhlbi.nih.gov

SUBMITTING AN APPLICATION

Applications must be prepared using the PHS 398 research grant 
application instructions and forms (rev. 5/2001).  The PHS 398 is 
available at http://grants.nih.gov/grants/funding/phs398/phs398.html in 
an interactive format.  For further assistance contact GrantsInfo, 
Telephone (301) 435-0714, Email:  GrantsInfo@nih.gov.
 
SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications 
requesting up to $250,000 per year in direct costs must be submitted in 
a modular grant format.  The modular grant format simplifies the 
preparation of the budget in these applications by limiting the level of 
budgetary detail.  Applicants request direct costs in $25,000 modules.  
Section C of the research grant application instructions for the PHS 398 
(rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html 
includes step-by-step guidance for preparing modular grants.  Additional 
information on modular grants is available at 
http://grants.nih.gov/grants/funding/modular/modular.htm.

USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 
5/2001) application form must be affixed to the bottom of the face page 
of the application.  Type the RFA number on the label.  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 and number must be typed on line 2 of the face 
page of the application form and the YES box must be marked. The RFA 
label is also available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf.
 
SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original 
of the application, including the Checklist, 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 as 
well as all five collated sets of Appendix material must be sent to:

Anne Clark, Ph.D.
Chief, Review Branch
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) 480-0730
Email:  ClarkA@nhlbi.nih.gov

Please note that applications delivered by individuals are no longer 
accepted; all applications must either come via courier delivery or the 
USPS (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-012.html).

APPLICATION PROCESSING: Applications must be received by the application 
receipt date listed in the heading of this RFA.  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.

Principal investigators should not sent supplementary material without 
first contacting the Scientific Review Administrator (SRA).  The SRA 
will be identified in the letter sent to you indicating that your 
application has been received.  If you have not received such a letter 
within three weeks after submitting the application, contact Dr. Anne 
Clark at the address listed under Inquiries.

PEER REVIEW PROCESS  
 
Upon receipt, applications will be reviewed for completeness by the CSR 
and responsiveness by the NHLBI.  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:

o Receive a written critique
o 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 and assigned a priority score
o Receive a second level review by the NHLBI and NIDDK National 
Advisory Councils. 
 
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 your application in order to judge the likelihood 
that the proposed research will have a substantial impact on the pursuit 
of these goals: 

o Significance 
o Approach 
o Innovation
o Investigator
o Environment
  
The scientific review group will address and consider each of these 
criteria in assigning your application=s overall score, weighting them 
as appropriate for each application.  Your 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, you 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 your study address an important problem? If the 
aims of your application are achieved, how do they advance scientific 
knowledge?  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?  Do you acknowledge potential problem areas and 
consider alternative tactics?

(3) INNOVATION: Does your project employ novel concepts, approaches or 
methods? Are the aims original and innovative?  Does your project 
challenge existing paradigms or develop new methodologies or technologies?

(4) INVESTIGATOR: Are you appropriately trained and well suited to carry 
out this work?  Is the work proposed appropriate to your experience 
level as the principal investigator and to that of other researchers (if any)?

(5) ENVIRONMENT: Does the scientific environment in which your 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?

ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your 
application will also be reviewed with respect to the following:

o PROTECTIONS:  The adequacy of the proposed protection for humans, 
animals, or the environment, to the extent they may be adversely 
affected by the project proposed in the application.

o INCLUSION: The adequacy of plans to include subjects from both 
genders, all racial and ethnic groups (and subgroups), and children as 
appropriate for the scientific goals of the research.  Plans for the 
recruitment and retention of subjects will also be evaluated. (See 
Inclusion Criteria included in the section on Federal Citations, below)

o DATA AND RESOURCE SHARING: The adequacy of the proposed plan to share 
data and/or resources, as appropriate for the scientific goals of 
the research. 

o BUDGET: The reasonableness of the proposed budget and the requested 
period of support in relation to the proposed research. 

RECEIPT AND REVIEW SCHEDULE

Letter of Intent Receipt Date:    May 20, 2002
Application Receipt Date:         June 19, 2002
Peer Review Date (estimated):     October/November, 2002
Council Review:                   February 6-7, 2003
Earliest Anticipated Start Date:  April 1, 2003

AWARD CRITERIA

Award criteria that will be used to make award decisions include:

o Scientific merit (as determined by peer review)
o Availability of funds
o Programmatic priorities.

REQUIRED FEDERAL CITATIONS 

INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy 
of the NIH that women and members of minority groups and their sub-
populations must be included in all NIH-supported clinical research 
projects unless a clear and compelling justification is provided 
indicating 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 clinical research should read the AMENDMENT 
"NIH Guidelines for Inclusion of Women and Minorities as Subjects in 
Clinical Research - Amended, October, 2001," published in the NIH Guide 
for Grants and Contracts on October 9, 2001 
(http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); 
a complete copy of the updated Guidelines are available at 
http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm.  
The amended policy incorporates: the use of an NIH definition 
of clinical research; updated racial and ethnic categories in 
compliance with the new OMB standards; clarification of language 
governing NIH-defined Phase III clinical trials consistent with the new 
PHS Form 398; and updated roles and responsibilities of NIH staff and 
the extramural community.  The policy continues to require for all NIH-
defined Phase III clinical trials that: a) all applications or 
proposals and/or protocols must provide a description of plans to 
conduct analyses, as appropriate, to address differences by sex/gender 
and/or racial/ethnic groups, including subgroups if applicable; and b) 
investigators must report annual accrual and progress in conducting 
analyses, as appropriate, by sex/gender and/or racial/ethnic group differences.

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN 
SUBJECTS: The NIH maintains a policy 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 is available at 
http://grants.nih.gov/grants/funding/children/children.htm.
 
REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS:
NIH policy requires education on the protection of human subject 
participants for all investigators submitting NIH proposals for 
research involving human subjects.  You will find this policy 
announcement in the NIH Guide for Grants and Contracts Announcement, 
dated June 5, 2000, at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html.

HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of 
research on hESCs can be found at 
http://grants.nih.gov/grants/stem_cells.htm and at 
http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html.  
Only research using hESC lines that are registered in the NIH Human 
Embryonic Stem Cell Registry will be eligible for Federal funding (see 
http://escr.nih.gov).  It is the responsibility of the applicant to 
provide the official NIH identifier(s)for the hESC line(s)to be used in 
the proposed research.  Applications that do not provide this 
information will be returned without review. 

PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: 
The Office of Management and Budget (OMB) Circular A-110 has been 
revised to provide public access to research data through the Freedom 
of Information Act (FOIA) under some circumstances.  Data that are (1) 
first produced in a project that is supported in whole or in part with 
Federal funds and (2) cited publicly and officially by a Federal agency 
in support of an action that has the force and effect of law (i.e., a 
regulation) may be accessed through FOIA.  It is important for 
applicants to understand the basic scope of this amendment.  NIH has 
provided guidance at 
http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm.

Applicants may wish to place data collected under this RFA in a public 
archive, which can provide protections for the data and manage the 
distribution for an indefinite period of time.  If so, the application 
should include a description of the archiving plan in the study design 
and include information about this in the budget justification section 
of the application.  In addition, applicants should think about how to 
structure informed consent statements and other human subjects 
procedures given the potential for wider use of data collected under 
this award.

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.  Furthermore, we caution reviewers that their 
anonymity may be compromised when they directly access an Internet site.

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 RFA is related to one or more of the priority areas. 
Potential applicants may obtain a copy of "Healthy People 2010" at  
http://www.health.gov/healthypeople.

AUTHORITY AND REGULATIONS: This program is described in the Catalog of 
Federal Domestic Assistance No. 93.837 (for DHVD/NHLBI), and No. 93.848 
(for DDDN/NIDDK) and is not subject to the intergovernmental review 
requirements of Executive Order 12372 or Health Systems Agency review. 
 
Awards are made under authorization of Sections 301 and 405 of the 
Public Health Service Act as amended (42 USC 241 and 284) and 
administered under NIH grants policies described at 
http://grants.nih.gov/grants/policy/policy.htm and under Federal 
Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 

The PHS strongly encourages all grant recipients to provide a smoke-
free workplace and discourage the 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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