GENESIS OF CARDIOMYOPATHY WITH HIV INFECTION AND ALCOHOL ABUSE

Release Date:  June 25, 1998

RFA:  HL-98-014

P.T.

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  November 15, 1998
Application Receipt Date:  January 15, 1999

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

PURPOSE

This solicitation invites research grants focused on the mechanisms
responsible for the additive or synergistic effects of alcohol
abuse and HIV infection in development of cardiomyopathy.  Studies
focusing on immunology, cellular and molecular mechanisms, and
genetic susceptibility are encouraged. Ultimately, the goal of this
solicitation is to provide a rational basis for the prevention,
optimal diagnosis, and therapy for the cardiovascular complications
of patients with HIV infection and alcohol abuse.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the
health promotion and disease prevention objectives of Healthy
People 2000, a PHS-led national activity for setting priority
areas.  This Request for Application (RFA), Genesis of
Cardiomyopathy with HIV Infection and Alcohol Abuse, is related to
the priority areas of alcohol and other drugs, maternal and infant
health, heart disease and stroke, HIV Infection, and sexually
transmitted diseases.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0 or
Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-512-1800).

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 PHS policy governing such awards.  HIV infection,
alcohol physiology, immunology, cardiovascular pathology,
biochemistry, genetics, cellular biology, and molecular biology 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)
individual research project grant (R01) mechanism of support. 
However, specific application instructions have been modified to
reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts
being examined by the NIH.  The modular grant concept establishes
specific modules in which direct costs may be requested as well as
a maximum level for requested budgets.  Only limited budgetary
information is required under this approach.  The just-in-time
concept allows applicants to submit certain information only when
there is a possibility for an award.  It is anticipated that these
changes will reduce the administrative burden for the applicants,
reviewers and Institute staff.

For this RFA, funds must be requested in $25,000 direct cost
modules with a maximum of 10 modules ($250,000 direct costs) per
R01 per year may be requested.  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 and any budget adjustments made by the
Initial Review Group will be in modules of $25,000.  Instructions
for completing the Biographical Sketch have also been modified.  In
addition, Other Support information and the application Checklist
page are not required as part of the initial application.  If there
is a possibility for an award, necessary budget, Other Support and
Checklist information will be requested by NHLBI staff following
the initial review.  The APPLICATION PROCEDURES section of this RFA
provides specific details of modifications to standard PHS 398
application kit instructions.  Responsibility for the planning,
direction, and execution of the proposed project will be solely
that of the applicant.  It is anticipated that support for this
program will begin in July 1, 1999.  Administrative adjustments in
project period and/or amount may be required at the time of the
award.

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.

FUNDS AVAILABLE

It is anticipated that for fiscal year 1999, approximately $2
millions total costs will be available for the first year of
support for this initiative.  Award of grants pursuant to this RFA
is contingent upon receipt of such funds for this purpose.  It is
anticipated that up to eight new grants will be awarded under this
program.  Applicants may request up to five years of support. The
specific number to be funded will depend on the merit and scope of
the applications received and on the availability of funds.  Direct
costs will be awarded in modules of $25,000, less any overlap or
other necessary administrative adjustments.  Facilities and
Administrative costs will be awarded based on the negotiated rates.

RESEARCH OBJECTIVES

Background

An estimated 14 million people worldwide are infected with HIV-1. 
It is estimated that by the year 2000, there will be 350,000 cases
of AIDS, the most severe form of HIV infection in the United
States.  As the survival time is increasing through use of more
effective therapies in HIV- infected patients, new complications
and manifestation of the disease are likely to develop.
Cardiovascular involvement can occur at any stage of HIV infection
and may involve any cardiovascular tissues.  In late-stage HIV
infection, dilated cardiomyopathy (DCM) is the most important
complication and is associated with global severe left ventricular
dysfunction.  This complication was first described a decade ago
and accounts for a large portion of the cardiovascular mortality
rate associated with AIDS in the United States, estimated to be
between 1 percent and 6 percent of infected patients.  In this
country, HIV cardiomyopathy is reported to be the fourth leading
cause of DCM in adults; behind idiopathic DCM, idiopathic
myocarditis, and coronary artery disease.  Half of these patients
die due to the disease within 6 to 12 months.  Patients who then
develop chronic congestive heart failure require specialized
cardiac care.  Of HIV-infected children referred for testing, more
than 90  percent have cardiovascular abnormalities.

Other common forms of symptomatic heart disease in HIV-1-infected
patients are pericardial effusion with cardiac tamponade,
ventricular arrhythmias leading to sudden cardiac death, and
systemic embolization caused by nonbacterial thrombotic
endocarditis or infective endocarditis.  Severe immunosuppression
and immune dysregulation appear to play a critical role in the
increased patient susceptibility to these cardiac-HIV
complications.  Increased susceptibility of HIV-infected patients
to development of cardiomyopathy is likely caused by multiple
factors.  The demographic and clinical characteristics of HIV-
infected patients who develop cardiomyopathy, as well as other
potential risk factors, are not well understood.

Alcohol abuse also represents a major health and social problem
imposing immense financial expenditures to our national health-care
delivery system.  Alcohol abusers represent approximately 10 to 15 
percent of the general population in North America.  Up to one-
third of chronic alcohol abusers have abnormal cardiac function or
structure.  The estimated prevalence for DCM, the most common form
of cardiomyopathy is nearly 40 per 100,000 individuals.  Alcohol
abuse alone may result in cardiovascular complications including:
cardiomyopathy, hypertrophy, arrhythmias, and hypertension. 
Excessive maternal alcohol intake is associated with birth defects. 
Alcoholic DCM is well recognized complication and is one of the
commonest causes of DCM in the western world.  Since both alcohol
abuse and AIDS are prevalent clinical problems frequently
coexisting in patients, both may contribute to the genesis of DCM. 
To explore the genesis of DCM in patients with HIV-1 infection and
alcohol abuse, the interplay between and relative contribution of
both must be evaluated.

The role of HIV infection in the development of cardiomyopathy has
been only recently recognized.  HIV-1 infected patients experience
bimodal disease expression, with some (up to 50%) patients
experiencing rapid HIV-1 disease progression and the remainder non-
rapid HIV-1 disease progression.  Recent work has indicated that a
deletion ()32) in the chemokine monocyte receptor may favor either
long-term survival or resistance to infection, presumably because
of the inability of the abnormal chemokine receptor to bind to
HIV-1 gp120.  The mechanisms for HIV-1 related cardiomyopathy may
derive from direct infection of the myocytes, or may be due to
indirect effects of secondary viral infection and abnormal
inflammatory mediators.  The first cell to become infected by HIV-1
is likely the monocyte, through gp120 co-binding to the CD4
molecule and CCR5 chemokine receptor.  Monocytes migrate to tissues
where they evolve into fixed macrophages capable of releasing
inflammatory mediators, including many chemokines and cytokines. 
Thus, the HIV-1 cardiac tissue macrophage is likely to play a role
in the etiology of HIV-1 cardiovascular disease.  More accurate
assessment of the impact of immunity, viral infection and genetic
mutations upon cardiovascular structure and function is required.

The respective roles of immune system and of alcohol in the
development of cardiomyopathy is complex.  Chronic alcohol
consumption has deleterious effects on cytokine release, immune
response, and host defense as well as nutritional status and
oxidative stress.  Alterations in immune responsiveness in the host
include functional impairments of granulocytes, macrophages and
both B and T lymphocytes.  Experimental studies show clear
similarities between immune dysfunctions caused by excessive
alcohol consumption and those observed after HIV-1 infection.  The
postulated mechanisms by which alcohol may increase the host's
susceptibility to HIV infection and subsequent development of AIDS
can be divided into two major groups: those that(i) directly
interfere in the normal functions of cell subsets primarily
responsible for initiation of the anti-retroviral defenses (i.e.,
CD8+ T-cells) or (ii) modulation of certain cytokines/chemokines,
or their receptor levels, which are target of HIV-1.  However,
there are no comparable data from human studies.  The role of
alcohol in the progression of established infection on HIV
replication and in the frequency and severity of opportunistic
infections also requires study.

The role of alcohol in the development of cardiomyopathy has been
the subject of many investigations.  Chronic excessive alcohol
ingestion can lead to structural alterations, including myocardial
fibrosis, disruption of the myofibrillary architecture, presence of
inflammatory cells and increased lipid deposits.  Together, these
abnormalities may result in alcoholic cardiomyopathy, which
includes defects in mitochondria architecture and myofibrillar
apparati, impaired cardiac contractility and biochemical
abnormalities.

There are many features and possible mechanisms responsible for the
development of cardiomyopathy.  In rats, alcohol ingestion reduces
cardiac myofibrillar protein content, supporting histological and
clinical studies showing reduced contractile elements.  These
contractile proteins include actin, myosin light chain, and myosin
heavy chain.  Down regulation of heat shock proteins in the heart
of alcohol-fed rats may result in poor assembly of synthesized
proteins or protein de-stabilization.  This poor contractile
function may result from alterations in cellular calcium, magnesium
or phosphate homeostasis, changes in the activity of sarcolemmal
ion channels, and alterations in the Calcium-ion permeability of
the sarcoplasmic reticulum.  The toxic effects of alcohol by-
products (e.g., acetaldehyde) or the formation of fatty acid ethyl
esters may also impair mitochondrial oxidative phosphorylation. 
Alcohol may also interact directly with membrane proteins and
receptors to alter their activity.  Alcohol modulates both cAMP-
dependent protein kinase (PKA)-mediated and protein kinase C (PKC)-
mediated signal transduction.  In addition, alcohol can induce
activation of alpha-PKC and epsilon-PKC reduce the levels of beta-
PKC which is implicated in regulation of gene expression and in
regulating L-type channels activity in the heart.

Maternal alcohol consumption is a principle cause of birth defects
and developmental disabilities in the United States and other
industrialized countries.  Infants with the most severe expression
of fetal alcohol syndrome have profound growth retardation,
neurological deficits, and congenital malformations.  Heart
abnormalities include atrial septal defect, ventricular septal
defect, and Tetralogy of Fallot.  The possible mechanisms whereby
alcohol affects fetal heart development include impairment of
neural crest migration; interference with vitamin A metabolism and
other retinoids; lowered folate and increased homocysteine levels;
deficiencies of thiamin, magnesium and zinc; and, altered cell
proliferation.  Furthermore, several reports suggested an increased
incidence in cardiovascular structural defects and alterations in
ventricular function in infants born to HIV-positive mothers. 
Whether this higher incidence of cardiac complications reflects
fetal infection during cardiovascular development, nonspecific
response to maternal infection, or other maternal cofactors is not
known.

The role of inflammatory system in the development of
cardiomyopathy has been suggested.  High circulating levels of
cytokines including TNF-alpha are likely involved in pathogenesis
of skeletal muscle wasting in AIDS, although the role in the
genesis of AIDS DCM is not clear.  If common cellular mechanisms
are operative in AIDS and alcoholic DCM, a similar degree of
enhanced myofibrillar protein turnover should be observed in
cardiac ventricular myocytes in AIDS patients.  HIV protease is
capable of degrading specific cardiomyocyte contractile proteins. 
Expression of specific viral proteins (such as prt or tat) within
cardiac myocytes may have direct effects on myocardial protein
metabolism.  Such myofibrillar proteolysis could induce
pathological alterations in myocyte architecture that may be
clinically relevant.  Acute or chronic alcohol exposure may also
have synergistic deleterious effects on myocardial contractile and
mitochondrial protein turnover in the AIDS patient.  The effects of
the virus on the heart may depend upon alcohol induced alteration
of myocardial structure involving the sarcoplasmic reticular
system, sarcolemma, contractile proteins, membrane lipids or
Calcium metabolism.

A relationship between alcohol and genetic system in the
development of cardiomyopathy has been proposed.  A potential
genetic predisposition to the development of cardiomyopathy is
suggested by the finding of a higher frequency of the HLA-B8
antigen in alcoholic cardiomyopathy than in those who have normal
heart function.  DCM is a clinically and genetically heterogeneous
disorder caused by a variety of insults.  Familial dilated
cardiomyopathy occurs in at least 20-30 percent of cases of DCM. 
The candidate genes for dominant DCM have been mapped and the
identification of the disease genes which are expected to encode
novel cardiac structural cytoskeletal proteins is in progress. 
Patients with mutations in the dystrophin gene, such as Duchenne or
Becker muscular dystrophy, develop skeletal myopathy and
cardiomyopathy.  Many cases of these two muscular dystrophies are
sporadic, indicating a high frequency of spontaneous mutations in
the dystrophin gene.  The effect of alcohol and/or HIV on these
structural/contractile proteins simulating mutations observed in
dystrophic syndromes could be important in the development of
cardiac dysfunction in these patients.  Other genetic causes to be
evaluated include the possible inherited defect in the viral
receptor proteins, potentially placing affected individuals at risk
for future virally-induced cardiac disease.

Based on experimental data on the role of alcohol or HIV in the
development of cardiomyopathy, it is reasonable to postulate that
there may be a significant interaction between the two putative
factors.  Since it has been shown that there are cytokine
abnormalities accompanying the immune activation in some
alcoholics, and since there is evidence of myocardial infiltration
by immune system cells in at least some patients with
myocardiopathy, alcohol-induced immune activation with cytokine
abnormalities is likely to be a possible contributing factor in an
alcohol effect on HIV myocardiopathy.  This is especially so if the
virus is present in myocytes.  Cell culture, animal models, and
transgenic and knockout mice provide unique experimental models
enabling to dissect the individual impact of HIV-1 and alcohol use. 
In animal models, alcohol use and retroviral infection have been
shown to act synergistically to increase loss of immunoregulatory
substances.  Among all the existing models of HIV-1/AIDS, the best
model which replicates human AIDS is thought to be the macaque
model.  Non-human primate models have been shown to express
pathologic changes in the heart many months after alcohol ingestion
and may be suitable to demonstrate concomitant viral infection. 
Cell culture experiments may also be applied to allow study of the
effect of individual or combinations of viral proteins in the
presence or absence of alcohol in cardiac myocytes, cardiac
fibroblasts, and endothelial cells, and to examine changes in cell
function and signaling events.  The findings could then be
correlated with those obtained in animal models and patients.

Proposed Research

The purpose of this new initiative is to invite grant applications
for research that examine the mechanisms responsible for the
development of cardiomyopathy in the setting of combined alcohol
abuse and HIV infection.  Studies focusing on immunology, cellular
and molecular mechanisms, genetic susceptibility, the role of
gender and race, and nutritional interactions are encouraged.  The
following topics are suggested as examples only.  Applicants are
urged to consider other topics within the scope of this
solicitation based on their knowledge of the field and their
particular research expertise.

o  Cardiac tissue sampling using biopsy (for adults) and autopsy
(for children and adults), i.e., monocyte/macrophage trophic HIV-1
strains, chemokine expression by myocytes/infiltrates, cytokine
production by inflammatory cell (mRNA, proteins); and myocardial
biopsy including the pathologic and immunopathologic review of
previously obtained autopsy material

o  Immune function testing, i.e., extended mononuclear cell
phenotyping, lymphocyte proliferation assay, cytotoxic T-cell
assay, immunoglobulin class switching, chemokine gene deletions;
immunology and virology of HIV-infected cells interacting directly
or indirectly with alcohol

o  Injury to myocardial cells and extracellular components,
including altered contractile protein turnover caused by alcohol,
antiviral agents, traditional medicines, and nutritional
deficiency; effects of HIV therapy in a background of alcoholism;
and injury from body defense response, i.e., cytokines,
mitochondrial toxicity

o  Role of myocardial cellular mechanisms and interaction with
endothelium, immune system and cytokine production, cell viability,
hypertrophy, signal transduction

o  Physiological mechanisms of myocardial dysfunction, i.e.,
ventricular function, myocyte contractility, heart rate, wall
thickness, stroke velocity index, fractional shortening, pump
function, vascular coupling

o  Interaction of viral elements and alcohol with cardiovascular
cells and effects on their functions; alterations of gene
expression of cardiac contractile proteins, calcium regulatory
proteins, and markers of cardiomyopathy and hypertrophy;
relationship between gene mutations of cardiac structural proteins
and the complications; identification of candidate genes for the
cardiomyopathy

o  Models: cell cultures, animal models and humans;  research in
the virology and immune response to associated viruses in the
alcohol model

o  Genetic susceptibility and congenital defects caused by alcohol
abuse or/and HIV infection, i.e., involvement of developmental
genes

These examples often overlap, and applicants may propose
multidisciplinary approaches to address more than one of these
areas.  This initiative will not support grants that focus on
epidemiological studies or clinical trials.

SPECIAL REQUIREMENTS

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

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of the NIH that women and members of minority
groups and their subpopulations must be included in all NIH
supported biomedical and behavioral research projects involving
human subjects, unless a clear and compelling rationale and
justification is provided that inclusion is inappropriate with
respect to the health of the subjects or the purpose of the
research.  This policy results from the NIH Revitalization Act of
1993 (Section 492B of Public Law 103-43).

All investigators proposing research involving human subjects
should read the "NIH Guidelines for Inclusion of Women and
Minorities as Subjects in Clinical Research," which have been
published in the Federal Register of March 28, 1994 (FR 59
14508-14513) and in the NIH Guide to Grants and Contracts, Volume
23, Number 11, March 18, 1994.

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

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN
SUBJECTS

It is the policy of NIH that children (i.e., individuals under the
age of 21) must be included in all human subjects research,
conducted or supported by the NIH, unless there are scientific and
ethical reasons not to include them.  This policy applies to all
initial (Type 1) applications submitted for receipt dates after
October 1, 1998.

All investigators proposing research involving human subjects
should read the "NIH Policy and Guidelines on the Inclusion of
Children as Participants in Research Involving Human Subjects" that
was published in the NIH Guide for Grants and Contracts, March 6,
1998, and is available at the following URL address:
https://grants.nih.gov/grants/guide/notice-files/not98-024.html

LETTER OF INTENT

Prospective applicants are asked to submit, by November 15, 1998,
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 NHLBI staff to estimate the potential
review workload and to avoid conflict of interest in the review.

The letter of intent is to be mailed, or faxed, 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
Email:  James_Scheirer@NIH.GOV

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) 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; 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: GrantsInfo@nih.gov; and on the internet at
https://grants.nih.gov/grants/funding/phs398/phs398.html.

The RFA label found in the PHS 398 (rev. 5/95) application kit 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 (Genesis of Cardiomyopathy
with HIV Infection and Alcohol Abuse) and number (HL-98-014) must
be typed on line 2 of the face page of the application form and the
YES box must be marked.

BUDGET INSTRUCTIONS
The total direct costs must be requested in accordance with the
program guidelines and the modifications made to the standard PHS
398 application instructions described below:

FACE PAGE
As a reminder, Items 7a and 8a should be completed to indicated
Modular Direct Costs requested and Items 7b and 8b should reflect
Total Costs (Modular Direct plus F&A costs).  Item 7 should reflect
costs for the Initial Budget Period and item 8 should reflect costs
for the Total Budget Period.

DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD
Do not complete Form Page 4 of the PHS 398 (rev 5/95).  It is not
required nor will it be accepted at the time of application.

BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT
Do not complete the categorical budget tables on page 5 of the PHS
398 (rev.  5/95) Form.  Only the requested total direct costs line
for each year should 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 10 modules ($250,000
direct cost) per year may be requested for each R01 application. 
Applicants may request for up to five years of support for this
RFA.  Direct cost budgets 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.

BUDGET JUSTIFICATION

o  Budget justifications should be provided under "Justifications"
on Form Page 5 of the PHS 398.

o  List the names, role on the project and proposed percent effort
for all project personnel (salaried or unsalaried)and provide a
narrative justification for each person based on his/her role on
the project.

o  Identify all consultants by name and organizational affiliation
and describe the services to be performed.

o  Provide a general narrative justification for individual
categories (equipment, supplies, etc.) required to complete the
work proposed.  More detailed justifications should be provided for
high cost items.  Any large one-time purchases, such as large
equipment requests, must be accommodated within these limits.

CONSORTIUM/CONTRACTUAL COSTS

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.  A letter of intent from each
collaborating institution should be submitted with the application. 
Only the percentage of the consortium/contractual TOTAL COSTS
(direct and facilities and administrative costs) relative to the
total DIRECT COSTS of the overall project needs to be stated at
this time.  The following example should be used to indicate the
percentage cost of the consortium, "The consortium agreement
represents 27% of overall direct costs requested in the first
year."  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 of 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.

BIOGRAPHICAL SKETCH

A biographical sketch is required for all key personnel, following
the modified instructions below.  Do not exceed the two-page limit
for each person.

o  Complete the educational block at the top of the form page;

o  List current position(s) and those previous positions directly
relevant to the application;

o  List selected peer-reviewed publications directly relevant to
the proposed project, with full citation;

o  The applicant has the option to provide information on research
projects completed and/or research grants participated in during
the last five years that are relevant to the proposed project.

OTHER SUPPORT - Do not complete the "Other Support" pages (Form
Page 7).  Selected other support information relevant to the
proposed research may be included in the Biographical Sketch as
indicated above.  Complete Other Support information will be
requested by NHLBI staff if there is a possibility for an award.

CHECKLIST

No "Checklist" page is required as part of the initial application. 
A completed Checklist will be requested by NHLBI staff if there is
a possibility for an award.

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.

Applications not conforming to these guidelines will be considered
unresponsive to this RFA and will be returned without further
review.

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

Applications must be received by January 15, 1999.  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 CSR
and responsiveness by NHLBI.  Incomplete and/or unresponsive
applications will be returned to the applicant without further
consideration.  Remaining applications may be subjected to a
streamlined review process by a Special Emphasis Panel convened by
NHLBI Scientific Review Office to determine their scientific merit
relative to other applications received in response to the RFA. 
The roster of reviewers for the RFA will be available on the NHLBI
home page approximately four weeks prior to the scheduled review
date.  Applications determined to be meritorious will be evaluated
for scientific and technical merit by the review committee, be
discussed and receive a priority score.  All other applications
will not be discussed or scored.  Secondary review of the
applications will be conducted by the National Heart, Lung, and
Blood Advisory Council (NHLBAC).

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 review, comments on
the following aspects of the application will be made 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 the assignment of the
overall score.

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?

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?

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.

AWARD CRITERIA

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 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.

Schedule

Letter of Intent Receipt Date:     November 15, 1998
Application Receipt Date:          January 15, 1999
Date of Initial Review:            March/April 1999
Review by NHLBI Advisory Council:  May 1999
Anticipated Award Date:            July 01, 1999

INQUIRIES

Inquiries concerning this RFA are encouraged.  Potential applicants
may request sample budget pages.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues and requests for
sample budget pages to:

Lan-Hsiang Wang, Ph.D.
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Rm 9148, MSC 7940
Bethesda, MD  20892-7940
Telephone:  (301) 435-0510
FAX:  (301) 480-1335
Email:  LW72F@nih.gov

Direct inquiries regarding fiscal matters to:

Mrs. Marie Willet
Grants Operations Branch
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 7156, MSC 7128
Bethesda, MD  20892-7128
Telephone:  (301) 435-0144
FAX:  (301) 480-3310
Email:  Marie_Willet@nih.gov

AUTHORITY AND REGULATIONS

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