Release Date:  October 5, 1999

RFA: HL-00-007

National Heart, Lung and Blood Institute
National Institute of Diabetes and Digestive and Kidney Diseases

Letter of Intent Receipt Date: December 15, 1999
Application Receipt Date: January 12, 2000



The objective of this initiative is to support research on the effects of HIV
protease inhibitors on lipid metabolism leading to hyperlipidemia and altered
body fat distribution, the onset of insulin resistance, and the development of
accelerated atherosclerosis.  Solicited programs should address the possible
basic mechanism(s) underlying the metabolic and hormonal alterations leading
dyslipidemias and lipodystrophy as well as insulin resistance observed in HIV-
positive patients undergoing protease inhibitor treatment and the relationship
between the development of these abnormal metabolic processes and the
accelerated progression of atherosclerosis.  The program requiresinvestigators
to engage in interdisciplinary and collaborative research focused on clinical
as well as basic studies. 

In addition, this program will foster collaborations among scientists with
different expertise, abilities, and talents to solve problems that require a
multifaceted approach, diverse skills, and special resources not typically
located within a single department or at a given institution.  Among the
disciplines and expertise that may be appropriate for this research program
are endocrinology, lipid metabolism, vascular medicine, clinical science,
treatment of HIV-AIDS, physiology, biochemistry, vascular  biology, pathology, 
molecular and cell biology, genetics, biostatistics, and imaging.  The collaborations
should focus on a common hypothesis with all component projects contributing
scientifically to the central theme.  The collaborative projects may include
shared resources as long as the interdependence and multi disciplinary nature
of the individual components is demonstrated.


The Public Health Service (PHS) is committed to achieving the health promotion
and disease prevention objectives of "Healthy People 2000," a PHS-led national
activity for setting priority areas.  This Request for Applications (RFA),
"Protease Inhibitor Related Atherosclerosis in HIV Infection", is related to
one or more of the priority areas.  Potential applicants may obtain a copy of
"Healthy People 2000" at


Applications may be submitted by domestic and foreign, for-profit and
non-profit organizations, public and private, such as universities, colleges, 
hospitals, laboratories, units of State and local governments, and eligible 
agencies of the Federal government.  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 PHS policy governing such awards.


This RFA will use the National Institutes of Health (NIH) research project
grant (R01) award mechanism to support collaborative research projects. 
Responsibility for the planning, direction, and execution of each of the
proposed projects will be solely that of the respective applicant.  The total
project period for an application submitted in response to this RFA may not
exceed 5 years.  This RFA is 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 July 1, 2000.

Applicants must propose a multi disciplinary program, comprising basic and
clinical science studies.  Investigators are encouraged to establish
collaborations to meet the objectives of this RFA.  Collaborative groups may
consist of either two or three research R01 projects consisting of basic
science and clinical studies, and have a common theme.  Interactions between 
basic and clinical scientists are expected to strengthen the research, enhance 
transfer of fundamental research findings to the clinical setting, and identify 
new research directions.  Plans for transfer of findings from basic to clinical 
studies should be described.  Applications not proposing both basic and clinical
research studies will not be responsive to this solicitation and will be
returned to the applicant without review.  

Collaborative R01 projects may be from a single institution or several
institutions, may include shared resources, and should demonstrate synergism
among the individual components.  If core support is requested, it should be
organized as a separate R01 application and submitted as part of the
collaboration, but its funding will be part of one of the research R01s.  The
funding decision will be influenced by the scientific merit of the individual
applications, the degree of collaboration between the investigators, the
approaches taken to meet the objectives of the RFA, and the programmatic
balance and needs of  National Heart, Lung and Blood Institute ( NHLBI ) and the
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK).  Although applicants are required to submit collaborative applications, 
the NHLBI and the NIDDK may choose to fund individual R01s outside the 
collaborative arrangement owing to their special scientific merit and programmatic 
needs and balance.

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 Grant applications can be
found at

For this RFA, funds must be requested in $25,000 direct cost modules.  A
feature of the modular grant concept is that no escalation is provided for future
years, and all anticipated expenses for all years of the project must be included
within the number of modules being requested.  Only limited budget information
will be required at submission and any budget adjustments made by the Initial
Review Group will be in modules of $25,000.

A group of collaborative R01 applications may request up to a total of 26
modules ($650,000 direct cost), per year for all component R01s, including
cores.  Costs of individual R01 components may be substantially different from
each other within a collaborative group.  Equipment is included in the budget
limitation.  However, requests for expensive special equipment that cause an
application to exceed this limit may be permitted on a case-by-case basis
following staff consultation.  Such equipment requires justification.  Final
decisions will depend on the nature of the justification and the availability
of funds.  Administrative adjustments in project period and/or amount may be
required at the time of the award.

Instructions for completing the Biographical Sketch have also been modified. 
In addition, Other Support information is not required as part of the initial
application.  If there is a possibility for an award, necessary budget and
Other Support information will be requested by institute program staff following 
the initial review.  The APPLICATION PROCEDURES section of this RFA provides specific
details of modifications to standard PHS 398 application kit instructions. 

Applicants that have a General Clinical Research Center (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.


The NHLBI and the NIDDK intend to commit approximately $6,000,000 in total
costs in FY 2000 to fund up to 14 new and/or competitive continuation grants in
response to this RFA either as part of collaborative projects or as individual
R01s.  Applicants may request a project period of up to 5 years and a budget
for direct costs of up to $650,000 per year for a group of collaborative R01
applications, excluding indirect costs on consortium arrangements.  Because
the nature and scope of the research proposed may vary, it is anticipated that the
size of each award R01 in the group 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, the receipt of a
sufficient number of applications of outstanding scientific and technical
merit, and the scope of applications received.  Direct costs will be awarded in
modules of $25,000, less any overlap or other necessary administrative adjustments. 
Facilities and Administrative costs (Indirect costs) will be awarded based on
the negotiated rates.   



HIV-AIDS is a devastating disease and was responsible for about 35,000 deaths
of relatively young people in the United States in 1996.  It is expected to
affect millions of patients with substantial health care costs.  Until recently, 
the main treatments utilized nucleoside and non-nucleoside analogs, which are
reverse transcriptase inhibitors, but had limited effect on the control or
treatment of the disease.  However, the discovery and use of HIV specific
protease inhibitors in treatment beginning in late1995 has initiated a new era
in the therapeutic management of the disease. Use of the protease inhibitors,
alone and in combination therapy, are credited with substantially decreasing
the number of American deaths from AIDS. 

The mechanism of action of the protease inhibitors is believed to be through
their binding to the active site of HIV protease thus inhibiting the activity
of the enzyme.  By preventing the cleavage of the viral polyproteins, only
immature non-infectious viral particles are formed resulting in a decrease in viral
RNA.  Four protease inhibitors are currently in use: saquinavir mesylate, ritonavir,
indinavir sulfate and nelfinavir.  Combinations of various protease inhibitors
with nucleoside and non-nucleoside reverse transcriptase inhibitors usually
have synergistic effects and are used effectively in clinical practice.

The successful use of protease inhibitors to lower plasma virus to
undetectable levels has led to the aggressive treatment of early HIV infection, 
before patients have experienced major clinical manifestations of the disease. 
Initial evidence demonstrated that the effects of therapy were dramatic and 
resulted in undetectable levels of virus in two to four months.  Recent evidence, 
however, indicates that although the virus is not detectable in a patient's blood 
some of the virus continues to exist in latent reservoirs.  Even after protease
inhibitor treatment for up to two years, virus particles can still be detected
in some cells.  These findings have led to the present recommendations that
protease inhibitor treatment be continued to suppress viral infection.  In
order to deplete latent stores of HIV, the protease inhibitor treatment may need to
be maintained for up to 10 years and possibly longer. 
With extended treatment, HIV-positive patients have been experiencing a high
prevalence of unexpected side effects.  The most serious of the side effects
include increases in cholesterol and triglyceride to levels where treatment to
decrease the risk of premature atherosclerosis and cardiovascular diseases
would be recommended.  The magnitude of the problem is alarming.  Prior to
treatment, 59% of HIV-positive patients who had never received a protease inhibitor 
had cholesterol and triglyceride values considered in the normal, healthy range. 
After treatment, only 7% of these patients had normal lipid values.  There
also have been reported cases of heart attack and angina in patients receiving
highly active antiviral therapy (HAART) treatment suggesting that premature
atherosclerosis may be occurring.  Atherosclerosis underlies most coronary
heart disease, a major cause of death (500,000 per year) and disability, as well as
much peripheral vascular disease, many cases of stroke, and several other
diseases.  Additional side effects that HIV-positive patients have experienced
during protease inhibitor treatment include loss of peripheral fat tissue
(lipodystrophy), and/or accumulation of fat intra-abdominally, in breast
tissue of women, and over the cervical vertebrae.  Also, insulin resistance has 
been reported.  The observed protease inhibitor side effects (dyslipidemias,
hyperglycemia, central adiposity, and lipodystrophy) suggest that protease
inhibitors cause major metabolic perturbations.  The mechanism(s) underlying
these changes is not known.

In normal individuals, there is a balance in the catabolism and synthesis of
cholesterol, triglyceride, and the proteins associated with them so that their
levels do not increase.  Triglycerides are readily hydrolyzed by lipoprotein
lipase resulting in fatty acids for energy or storage in adipose tissue. 
Lipoprotein lipase is known to be regulated by insulin.  The remaining
lipoprotein, enriched in cholesterol is removed primarily by receptors in the
liver.  Lipoprotein metabolism may be altered by a functional deficiency in
the key apoproteins, tissue receptors or enzymes due to genetic mutations.  A
functional deficiency of lipoprotein lipase can result in very high plasma
triglyceride levels and decreased high density lipoprotein (HDL) levels. 
Absence of functional receptors results in the accumulation of plasma
cholesterol due to a lack of removal of the cholesterol-rich lipoproteins.  It
is not known whether the lipid changes observed with protease inhibitor
therapy are due to altered synthesis or catabolism of the lipids directly, or reflect
changes in lipoprotein receptor function or lipoprotein metabolizing enzymes. 
Furthermore, it is not clear whether those patients who respond most
dramatically to the protease inhibitors have a genetic predisposition to
altered lipid metabolism.

It has been suggested that protease inhibitors may be interfering with the
activity and levels of the gene expression of some of the known lipoprotein
receptors.  For example, it has been observed that the 12 amino acids spanning
the catalytic site of HIV-1 protease have a 70% homology with the low density
lipoprotein receptor-related protein, a hepatic scavenger of circulating
lipids.  This homology might mean that the protease inhibitors could bind to and
interfere with the proper functioning of the receptor leading to increased
plasma lipid levels.  Alternatively, there are systems in the body that depend
on protease enzymes to function and perhaps the protease inhibitors impair
these enzymes. There has been little or no work done to determine the interaction
between protease inhibitors and proteins that regulate lipid metabolism such
as the lipases, cholesterol ester transfer protein, and the receptors. 

The various fat depots differ metabolically, and healthy individuals with
upper-body (central) obesity are prone to metabolic and cardiovascular
complications.  In non-HIV positive subjects, insulin resistance correlates closely 
with abdominal obesity and hypertriglyceridemia and underlies the development of
type 2 (non-insulin dependent) diabetes mellitus.  These are fundamentally
important differences that are thought to be related to the visceral adipose tissue
being drained by the portal venous system with a direct connection with the liver. 
Thus, patients with upper-body obesity commonly develop dyslipidemia,
hyperglycemia, and hyperinsulinemia.  HIV-positive patients treated with
protease inhibitors have reported substantial decreases in total body fat with
peripheral lipodystrophy (fat wasting of the face and limbs) and relative
conservation or enhancement of central adiposity in contrast to HIV-infected
patients that have not been treated with these inhibitors.  Often the HIV-
positive patients with lipodystrophy due to protease inhibitor therapy also
have significantly higher triglyceride, cholesterol, insulin and C-peptide levels
and are more insulin-resistant than protease inhibitor recipients without
lipodystrophy.  The increases in triglyceride levels can appear concomitantly
with the peripheral lipodystrophy, but independently of elevated cholesterol
levels.  In some cases both triglyceride levels and abnormal fat deposition
may be reversed by switching therapy to a different protease inhibitor.  These
observations have led to the hypothesis that use of the protease inhibitors
may be associated with the development of a new syndrome consisting of peripheral
lipodystrophy, hyperlipidemia and insulin resistance.  This hypothesis needs
to be carefully examined especially since none of the mechanisms involved in or
responsible for these side effects has been studied in any detail.  There have
been no studies to determine if the elevated plasma triglyceride levels
reflect the active remodeling of particular adipose tissue stores.  The mechanism(s)
by which the protease inhibitors could selectively target adipose tissue depots
is not known.

Diabetes and hyperglycemia were reported in varying degrees with use of all
four protease inhibitors.  In some patients with dyslipidemia and lipodystrophy,
there is evidence of insulin resistance.  In a recent study, some protease
inhibitor recipients had worsening or new diabetes mellitus.  For the long-
standing, type 1 (insulin-dependent) diabetic patient, daily insulin
requirements increased by 70%.  In the new diabetics, insulin was required for
symptomatic hyperglycemia after 4 weeks of indinavir.  Other patients had
asymptomatic hyperglycemia 4 weeks after switching from indinavir to
ritonavir-saquinavir.  Thus, it seems that protease inhibitors can be associated 
with a non-ketosis-prone hyperglycemia that occurs 1-7 months after starting
treatment.  The mechanism of protease inhibitor-associated hyperglycemia is unknown, 
and its role in accelerated atherosclerosis and coronary heart disease needs to be
systematically examined.

If these secondary problems associated with protease inhibitors cannot be
resolved, the potential impact on the management of HIV-positive patients is
far reaching.  In the general population, the first approach to lower plasma
cholesterol levels involves lifestyle changes such as lowering fat and
cholesterol content of the diet, decreasing body weight if obese, and
increasing exercise.  To lower fasting triglyceride levels and increase HDL levels 
the first approach includes weight loss if overweight, lowering excessive alcohol
intake, lowering fat content of the diet, lowering the simple sugar content of
the diet, and increasing exercise.  The next approach for patients with low
HDL and high triglyceride levels is to use gemfibozil or nicotinic acid.  The
normal approaches to lipid management may not be as successful in patients receiving
protease inhibitors. Research is needed to determine which drugs are most
appropriate.  Statins are the most potent of cholesterol lowering drugs, and
act directly by inhibiting cholesterol synthesis.  However, statins may not be as
effective in patients on protease inhibitors and greater caution needs to be
exerted with their use since protease inhibitors may interfere with the
metabolic pathway for statins in the liver.  In fact these agents may act
synergistically so that a potential side effect of the statins,
rhabdomyolysis, may be more common in HIV-positive patients receiving protease 
inhibitor therapy.  It is not clear if this is due to drug resistance.  The 
difficulties in treating the hyperlipidemia associated with protease inhibitors 
create challenging problems for managing these patients which will need a systematic
approach and careful study. 

High levels of glucose and insulin in the blood, and high levels of triglycerides 
and other lipids, are considered risk factors for atherosclerosis
associated with the use of protease inhibitors.  HDL levels are decreased in
patients receiving protease inhibitors and the mechanism responsible is not
known.  The relationships and the biological mechanisms by which these
protease inhibitors might influence insulin regulation, body fat redistribution, serum
lipid elevation and metabolism are not known.  This observation needs to be
further investigated.

Distal and proximal vascular lesions of the coronary arteries were observed in
autopsied HIV-seropositive patients.  These lesions were marked by major
eccentric atherosclerosis (with 80-90% obstruction of the arterial lumen) or
by fibrosis two-fold or six-fold the thickness of the tunica media.  Coronary
angiography documented severe premature atherosclerosis in young AIDS patients
on protease inhibitors.  Although there are reports of a few cases of coronary
atherosclerosis in AIDS adults, whose life span is expected to increase in
response to protease inhibitor treatment, the cardiovascular risk factors, the
severity of atherosclerosis and associated fibrosis suggest that the AIDS
virus plays an important role in the onset of the lesions.  Other infectious agents
have also been suggested to contribute to atherosclerosis.  With HIV-
seropositive patients, this may be augmented by the unfavorable lipid profile
and onset of diabetes due to treatment with protease inhibitors.  The cellular
and molecular events that are responsible for these effects and the related
changes in the vasculature need to be explored in more detail.

Thus, the increased life expectancy provided HIV-positive patients by the use
of protease inhibitors may be jeopardized or at least complicated by their being
at greater risk for developing cardiovascular diseases.  It is not clear how or
why protease inhibitors may lead to unfavorable changes in lipid and carbohydrate
metabolism, but these side effects alter the impact of protease inhibitors in
the treatment of HIV-positive patients and the successful management of AIDS. 
The side effects are a critical issue because HIV-positive patients who have
discontinued protease inhibitor treatment due to concerns about the increased
risk for coronary heart disease, diabetes, or altered fat distribution have
experienced an increase in viral load and the clinical manifestations of the
disease.  Patients that continue therapy with the protease inhibitors face
more complicated treatment schedules to manage the lipid and carbohydrate side
effects.  The basic mechanism(s) involved in the altered metabolism needs to
be determined to facilitate the management of HIV-positive patients and help in
the rational development of therapies for the treatment and prevention of
premature atherosclerosis and other cardiovascular diseases in protease inhibitor
treated patients.


It is proposed to support up to 14 R01s either as part of collaborative
projects or as individual R01 projects for research into the pathogenesis of
atherosclerosis in HIV-positive patients treated with protease inhibitors,
especially research that relates to the basic mechanisms underlying the
altered lipid metabolism and body fat distribution and the development of
atherosclerosis.  Applications must be multi disciplinary.  Furthermore, to
achieve its objectives and to accelerate the transition from bench to
bed-side, this RFA requires applicants to propose basic as well as clinical studies
during the grant cycle.  Applicants are strongly encouraged to establish
collaborations to augment their basic or clinical proposals to meet the objectives 
of the RFA.  The funding decision will be influenced by the scientific merit of the
individual applications, the degree of collaboration between the
investigators, the approaches taken to meet the objectives of the RFA, and the 
programmatic balance and needs of NHLBI and NIDDK.

Proposed Research

The known information on the dyslipidemias and lipodystrophy associated with
protease inhibitor therapy for HIV-positive patients is derived from clinical
observations.  Little is known about the basic science or mechanisms causing
these syndromes or side effects.  It is desired that the proposed research
have a broad base of interdisciplinary studies to address these problems.  It is
expected that the various side effects of protease inhibitors will encourage
investigators with expertise in a variety of disciplines to focus on lipid
metabolism and possible alterations due to protease inhibitors, and to
integrate these studies with approaches involving vascular cell biology, 
tissue-specific pathology, clinical investigations, and molecular biology 
(gene expression and regulation).  Physicians specializing in cardiology, lipid 
metabolism, diabetes, treatment of HIV-AIDS, and vascular medicine as well as basic 
scientists focusing on corresponding areas would be the most appropriate to collaborate
in this research.  A more detailed analysis of factors influencing the lipid
metabolic pathway, especially new approaches for clinical management, is also
likely to generate new testable hypotheses.  The cause of dyslipidemia and
type 2 diabetes mellitus in patients treated with protease inhibitors needs careful
and systematic investigation. 

Appropriate topics for investigation would include, but are not limited to,
the following:

o  Altered lipid metabolism resulting in dyslipidemia in HIV-positive patients
in response to protease inhibitor therapy.  Proposals may include metabolic and 
enzymatic studies to determine the cause of the elevated total cholesterol due 
to increased low density lipoprotein cholesterol with decreased HDL cholesterol 
levels associated with protease inhibitor therapy.  Studies of the effects of 
protease inhibitors on lipoprotein receptors and other regulatory molecules involved 
in lipid metabolism.  
 o  Elevated triglyceride levels in HIV-positive patients in response to
protease inhibitor therapy.  Studies will need to control for potential lipid 
alterations due to secondary infections and distinguish this from potential minor 
changes from the presence of HIV.  Studies may include metabolic approaches and 
enzymatic studies to determine if altered synthesis or degradation is
involved.  Studies relating the elevated triglyceride levels to changes in
adipose tissue metabolism and insulin  resistance are also relevant.

o  Changes in adipose tissue in HIV-positive patients in response to protease 
inhibitor therapy resulting in loss of peripheral and increases in intra-abdominal 
adipose tissue masses.  Studies may include the effects of protease inhibitors on 
the enzymes, receptors, and hormones important in regulation of specific adipose 
tissue depots.

o  The effect of protease inhibitors on vascular wall cells and atherogenesis. 
Basic studies may include effects on the autocrine and paracrine systems including 
endothelial cell activation and other reactions involved in atherogenesis.  
Studies of vascular cell biology are  appropriate.

o  Basic studies to determine the underlying mechanisms involved in the
observed responses in lipid and carbohydrate metabolic to protease  inhibitors.  
Studies to examine the role of receptors, signal transduction, and other cell 
regulatory mechanisms are appropriate.  The use of suitable animal models, cell 
studies and in vitro systems are encouraged.  

o  Clinical studies to determine the effect of protease inhibitors on
premature atherosclerosis and coronary heart disease in HIV positive patients. 
Studies will need to control for the potential contribution of secondary
infections to the development of atherosclerosis.  Approaches may include
imaging to determine the progression, stability, regression of lesions using
angiography and other non-invasive modalities.

o  Correlates of dyslipidemia and other risk factors of coronary heart
disease.  Adipose tissue abnormalities with protease inhibitors and
dyslipidemia.  Relationship of fat deposits over the cervical vertebrae
(buffalo hump) with protease inhibitor therapy to sterol metabolism. 

o  Dose dependence on the severity of the lipid response to the various
protease inhibitors and how this correlates with their potency or uptake. 

Because of the interdisciplinary nature of the research, collaboration among
investigators of varied expertise within the same or different institution is
strongly encouraged.  Specifically, "Networking" (i.e., shared biologic and
information resources, reagents, patients, and the like), should be
established to prevent duplication of efforts and to maximize benefits in the
most cost-efficient manner possible.  The applicants may request special modifications
to their equipment or additional small equipment for the safe handling of
HIV-positive samples if this is a new aspect of their research.


This RFA is intended to support multi disciplinary collaborative R01 research
programs.  Proposals including only basic or only clinical research will not
be responsive to this announcement and will be returned without review.  In
addition, clinical research projects focused on large epidemiological studies
or large clinical trials will be considered unresponsive to this initiative.


Each collaborative R01 program grant application and award must include
research involving human studies.  Support may be provided for human
biomedical studies of etiology, pathogenesis, prevention and prevention
strategies, diagnostic approaches, and treatment of diseases, disorders or
conditions.  Small population-based studies, where the research can be
completed within five years, may also be proposed. 

Upon initiation of the program, annual meetings will be held to encourage
exchange of information among investigators who participate in this program. 
A major goal of these meetings is to facilitate progress by providing a forum
that will lead to sharing ideas, technology, data, skills, and biological
materials.  Applicants must budget for travel funds that will allow principal
investigators and other key research scientists to participate in these


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 was published in the Federal Register of March 28, 1994 (FR
59 14508-14513) and in the NIH Guide for Grants and Contracts, Vol. 23, No.
11, March 18, 1994, available on the web at:


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

Investigators also may obtain copies of these policies from the program staff
listed under INQUIRIES.  Program staff may also provide additional relevant
information concerning the policy.


Prospective applicants are asked to submit a letter of intent by December 15,
1999, 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
NHLBI staff to estimate the potential review workload and avoid conflict of
interest in the review.

The letter of intent is to be mailed, or faxed, by the letter of intent
receipt date listed in the heading of this RFA to: 

Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7220, MSC 7924
Bethesda, MD 20892-7924
Telephone: (301) 435-0266
FAX: (301) 480-3541


The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  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 301/710-0267, email:

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.

The RFA label available 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
(HL-00-007) 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: has 
been modified to allow for this change.  Please note this is in pdf format.

State on the face page, Title Line (line 1), of each application that the
submission is part of a "Collaborative R01".  The individual components and
cores must be submitted as one package accompanied by a cover letter that
lists the principal investigators of each R01.  Include this letter with each
of the individual R01s, and in each R01 list the collaborating projects and
principal investigators on page 2, under "Performance Sites".  In addition, the
description section for each R01 within a collaborative R01 should be the same
and the applicants should define how and why the individual participants
propose to collaborate.  Applicants should elaborate on the significance and
nature of the collaboration in an Introduction section of the "Research Plan"
of each component R01.

Sample budgets and justification page will be provided upon request from Ms.
Jane Davis at the address listed under INQUIRIES.

Submit a signed, typewritten original of the application, including the
Checklist, and three signed, photocopies, in one package to:

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. C. James Scheirer, at the address listed under LETTER OF INTENT.

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.


Modular Grant applications will request direct costs in $25,000 modules, up to
a total direct cost request of $650,000 per year for all component R01s,
including cores.  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) 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.

4 of the PHS 398. It is not required and will not be accepted with the

categorical budget table on Form Page 5 of the PHS 398.  It is not required
and will not be accepted with the application.  Only the requested total direct
costs line for each year must be completed based on the number of $25,000
modules being requested.  Applicants may not request a change in the amount of
each module.  A maximum of 26 modules ($650,000 direct costs) for the entire
collaborative package, including cores, per year may be requested.  Applicants
may request up to 5 years of support for this RFA.  Direct cost budgets
typically will remain constant throughout the life of the project (i.e., the
same number of modules requested for all budget periods).  Any necessary
escalation should be considered when determining the number of modules to be
requested.  However, in the event that the number of modules requested must
change in any future year due to the nature of the research proposed,
appropriate justification must be provided.  Total Direct Costs for the Entire
Proposed Project Period should be shown in the box provided. 

o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative
page. (See
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.  Provide a narrative justification for each
person (including consultants) based on his/her role 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.

If collaborations or subcontracts are involved that require transfer of funds
from the grantee to other institutions, it is necessary to establish formal
subcontract agreements with each collaborating institution.  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.  A budget justification for the consortium
should be provided as described in the "Budget Justification" section above
(no Form Page 5 required for the consortium).  Please indicate whether the
consortium will be in place for the entire project period and identify any
future year changes in the percentage relative to the parent grant.

If there is a possibility for an award, the applicant will be requested to
identify actual direct and indirect costs for all years of the consortium. 
Please note that total subcontract costs need not be calculated in $25,000
modules.  However, when subcontract funds are added to the parent grant
budget, the total direct cost amount must be included in the number of $25,000 
modules requested.

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:

- 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. 


Upon receipt, applications will be reviewed for completeness by the CSR and
responsiveness by the 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.  The roster of
reviewers for the RFA will be available on the NHLBI home page approximately
four weeks prior to the scheduled review date.  The initial review group will
evaluate all applications as individual investigator-initiated grant
applications.  Additionally, the initial review group will consider in their
evaluation the overall strength and likelihood of effective collaboration of
each collaborative program.  As part of the initial merit review, a process
will be used by the initial review group in which applications 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 National Heart, Lung, and Blood Advisory Council. 

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

(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?

(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 any)?

(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?

(6) Collaboration:  Do the submitted R01 projects represent collaborative
research among investigators from different disciplines?  What are the
likelihood of effective collaboration among the investigators, and the
likelihood of success of the research objectives proposed?

The personnel category will be reviewed for appropriate staffing based on the
requested percent effort.  The direct costs budget request will be reviewed
for consistency with the proposed methods and specific aims.  Any budgetary
adjustments recommended by the reviewers will be in $25,000 modules.  The
duration of support will be reviewed to determine if it is appropriate to
ensure successful completion of the requested scope of the project

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

o  The 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 in relation to the
proposed research.

o  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.


Letter of Intent Receipt Date: December 15, 1999
Application Receipt Date: January 12, 2000
Peer Review Date: February/March, 2000
Council Review: May 18-19, 2000
Earliest Anticipated Start Date: July 1, 2000


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.

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 the awarding Institutes in making 
funding recommendations.  The Institutes may fund individual applications based 
on a number of considerations, the most important of which are based on their 
scientific merit and their importance in meeting the objectives of the RFA.  
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 and NIDDK are likely to select the more cost
competitive application for funding.


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

Direct inquiries regarding programmatic issues to:

Deborah Applebaum-Bowden, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10184, MSC 7956
Bethesda, MD  20892-7956
Telephone:  (301)435-0550
FAX: 301/480-2858

Philip F. Smith, Ph.D.
Division of Diabetes, Endocrinology, and Metabolic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 5AN-12C
45 Center Dr MSC 6600
Bethesda MD 20892-6600
Telephone: (301)594-8816

Direct inquiries regarding fiscal matters to:

Ms. Jane Davis
Division Extramural Affairs
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7926
Bethesda, MD  20892-7926
Telephone: (301) 435-0166
FAX: (301) 480-3310

Mr. Kieran Kelley
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, MSC 6600
Bethesda, MD 20892-6600
Telephone:  (301) 594-0417
FAX: (301) 480-3504


This program is described in the Catalog of Federal Domestic Assistance No.
93.837 and 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 PHS strongly encourages all grant 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

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