Full Text HL-95-006

SPECIALIZED CENTERS OF RESEARCH IN MOLECULAR MEDICINE AND
ATHEROSCLEROSIS

NIH GUIDE, Volume 23, Number 35, October 7, 1994

RFA:  HL-95-006

P.T. 04

Keywords: 
  Cardiovascular Diseases 
  Biology, Molecular 
  Pathophysiology 
  Disease Model 
  Gene Therapy+ 


National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  October 9, 1995
Application Receipt Date:  December 8, 1995

PURPOSE

This solicitation invites new grant applications to enter into a single
open competition for Specialized Centers of Research (SCOR) in
Molecular Medicine and Atherosclerosis.  The goals of the program are
to advance the understanding of the etiology and pathobiology of the
atherosclerotic lesion at the molecular level through the modern
methods and approaches of molecular medicine.  Molecular medicine
represents a paradigm shift to more systematic targeting and design of
clinical interventions based upon detailed and sophisticated molecular
information.  It embraces strategies aimed at understanding the
molecular basis of disease, and at studying how the structure and
activity of living cells are controlled by molecules such as DNA and
proteins.

A SCOR provides the opportunity for investigators to engage in
interdisciplinary and collaborative research that is focused on a
specific disease or an area within a disease category.  It is required
that SCOR applications include studies of human subjects and/or human
materials as well as basic studies clearly related to a disease area.
The foundation of the clinical component should be strongly linked to
the basic science projects; the basic science studies should be driven
by the needs of the clinical projects.  Thus, a SCOR has a central
theme to which all research projects pertain.  In addition, a SCOR may
include core units to provide services to the various research projects
and to support the organizational and administrative aspects of the
program.

Previous generations of the SCOR in Arteriosclerosis have contributed
significantly to the understanding of the basic mechanisms responsible
for the development of atherosclerosis, and clarified the role of major
risk factors such as blood cholesterol and specific lipoproteins and
apoproteins in atherogenesis.  The objectives of this new cycle of
SCORs are to focus on studies on the pathobiology of the
atherosclerotic lesion specially at the level of the arterial wall.
Such studies may include investigations of the mechanisms for lesion
susceptibility and initiation; the mechanisms of lesion progression,
complication, and regression; and the interactions of the vessel wall
with lipoproteins and other systemic factors promoting atherogenesis.
The new program emphasizes a shift away from studies with an exclusive
focus on the structure and function of lipids and lipoproteins.  The
means for acquiring this new knowledge would involve exploitation of
new techniques and strategies of molecular medicine such as gene
transfer and gene mapping and identification, three-dimensional
structural biology, vascular imaging, genetically modified animal
models, and gene therapy, which can yield information that heretofore
was inaccessible.  All these techniques are complemented by clinical
research disciplines as appropriate.

Coronary Heart Disease (CHD) accounts for the largest share of deaths
from diseases of the heart.  CHD rates are particularly high in blacks,
perhaps due to the higher prevalence of major CHD risk factors such as
hypertension, diabetes and obesity.  Differences in the nature of the
atherosclerotic process leading to CHD in blacks may also be a
contributory factor.  The National Heart, Lung, and Blood Institute
(NHLBI) wishes to encourage research into the pathogenesis of the
atherosclerotic lesion in blacks as part of this SCOR program.

To chart a course for future research, the NHLBI convened a working
group, which released a report in March 1994 on RESEARCH IN CORONARY
HEART DISEASE IN BLACKS.  This report provides specific recommendations
for future research in black populations.  The NHLBI wishes to strongly
encourage research into the pathogenesis of the atherosclerotic lesion
in women, Blacks and other minorities as part of this SCOR program and
recommends that this report, in particular, be consulted.

In addition, to encourage women and underrepresented minority
investigators to work within a SCOR project, to facilitate recruitment
of new scientists to this area of research, and to foster cutting edge
and innovative research directions, each SCOR program may support up to
two investigators by utilizing up to $50,000 per year per investigator
to fund pilot and feasibility projects.  This will allow
underrepresented minority investigators to acquire the skills and data
to become more competitive in seeking independent research support
(e.g., R01, R29).  These funds will not be supplements, but rather
specific dollars identified in the SCOR budget and restricted to be
used for this purpose.  The recipients would be chosen based on a
proposal written by a SCOR investigator and reviewed by an internal
review committee at the parent institution.

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 RFA,
Specialized Centers of Research in Molecular Medicine and
Atherosclerosis, is related to the priority area of heart disease and
stroke.  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 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by for-profit and non-profit domestic
institutions, public and private, such as universities, colleges,
hospitals, laboratories, units of State and local goverrnments, and
eligible agencies of the Federal government.  Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as Principal Investigators.  Awards will not be made to foreign
institutions.  However, under exceptional circumstances, a foreign
component critical to a project may be included as a part of that
project.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) specialized
center of research (P50) grant mechanism.  Responsibility for planning
the proposed project will be solely that of the applicant.  The total
project period of applications submitted in response to the present RFA
may not exceed five years.  The anticipated date of award is December
1, 1996.

Upon initiation of the program, there will be required communications
between SCORs, usually in the setting of a biennial combined meeting of
SCOR participants.  Applicants should request travel funds for this
purpose in fiscal years 1997, 1999, and 2001 of the budget.  Applicants
should also include a statement in their applications indicating their
willingness to participate in these meetings.

The principal investigator should be an established research scientist
with the ability to ensure quality control and the experience to
administer effectively and integrate all components of the program.  A
minimum time commitment of 25 percent is expected for this individual.
The principal investigator must also be the project leader of one of
the component research projects.  If, through peer review, this project
is not recommended for further consideration, the overall SCOR
application will not be considered further.  If this project is judged
by peer review to be of low scientific merit, it will markedly reduce
the overall scientific merit ranking assigned to the entire application
by the review committee.  Project leaders must agree to commit at least
20 percent effort to each project for which they are responsible.

This RFA is intended to support Specialized Centers of Research grants.
Therefore, applications that include only basic or only clinical
research will not be responsive to this RFA.  In addition, clinical
research projects focused on large epidemiological studies or large
clinical trials will be considered unresponsive to this RFA.

This new SCOR program focuses on studies of the atherosclerotic lesion
at the level of the arterial wall. Thus, studies with exclusive focus
on the structure and function of lipoproteins will be considered
unresponsive to this RFA.

Applicants should be aware that applications for supplemental funds
will be accepted only under unusual and well defined circumstances.
For example, the NHLBI may provide supplements to Centers to continue
a project not funded for the entire project period.  NHLBI staff should
be consulted prior to submission of an application.  Supplemental
grants for these purposes will not be awarded for the first 18 months
or the last 12 months of a total project period.

Length of SCOR Programs

Each NHLBI SCOR program be limited to ten years of support.  Exceptions
to this policy will be made only if a thorough evaluation of needs and
opportunities, conducted by a committee composed of non-federal
experts, determines that there are extraordinarily important reasons to
continue a specific SCOR program.

Under this policy, a given SCOR grant is awarded for a five-year
project period following an open competition.  Only one five-year
competing renewal is permitted, for a total of ten years of support,
unless the SCOR program is recommended for extension.

The NHLBI comprehensive evaluation of the SCOR program in Molecular
Medicine and Atherosclerosis will be conducted during the second
project period according to the following timetable.

Announcement SCOR competition       FY 1995
Project Period (First Competition)  FY 1997 to FY 2001
Program Re-announcement             FY 1999
Project Period (Second Competition) FY 2002 to FY 2006
Letters to SCOR Directors regarding
SCOR evaluation Plans               FY 2004 (mid-way through
                                       year 02 of 2nd
                                       project period)
SCOR Evaluation Meeting             FY 2004 (Late in year 02
                                       of project period)
Notification of SCOR Directors of
NHLBI decision                      FY 2004 (mid-way through
                                       year 03 of 2nd
                                       project period)

The NHLBI does not limit the number of SCOR applications in a given
SCOR program from one institution provided there is a different SCOR
principal investigator for each application and each application is
self-contained and independent of the other(s).  This does not preclude
cooperation planned or possible among participants of SCORs after
awards are made.  Scientific overlap among applications will not be
accepted.  If more than one application is envisioned from an
institution, the institution is encouraged to discuss its plans with
the NHLBI SCOR program administrator.

Consortium Arrangements

If a grant application includes research activities that involve
institutions other than the grantee institution, the program is
considered a consortium effort.  Such activities may be included in a
SCOR grant application, but it is imperative that a consortium
application be prepared so that the programmatic, fiscal, and
administrative considerations are explained fully.  The published
policy governing consortia is available in the business offices of
institutions that are eligible to receive Federal grants-in- aid.
Consult the latest published policy governing consortia before
developing the application.  If clarification of the policy is needed,
contact Mr. William Darby, Section Chief, Grants Operation Branch,
NHLBI, (301)594-7458.  Applicants should exercise great diligence in
preserving the interactions of the participants and the integration of
the consortium project(s) with those of the parent institution, because
synergism and cohesiveness can be diminished when projects are located
outside the group at the parent institution.  Indirect costs paid as
part of a consortium agreement are excluded from the limit on the
amount of direct costs that can be requested.

FUNDS AVAILABLE

Applicants may request up to $1,170,000 direct costs, not including
indirect costs for collaborating institutions, in the first year, with
a maximum increase of no more than four percent in each future year
requested in the application. It is anticipated that seven SCOR grants,
for a five year project period, at an estimated first year total cost
of $12.285 million, will be supported.

Award of grants pursuant to this RFA is contingent upon receipt of
funds for this purpose.  Designated funding levels are subject to
change at any time prior to final award, due to unforeseen budgetary,
administrative, and/or scientific developments.

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.

RESEARCH OBJECTIVES

Background

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.
Atherosclerosis is a multifactorial process with a complex and
incompletely understood etiology.  An interdisciplinary approach
integrating basic sciences with the clinical aspects of the disease is
required to study this disorder, and the NHLBI adopted the SCOR
mechanism in 1971 for that purpose.

Since their inception, the SCORs in Arteriosclerosis have promoted
multidisciplinary research on the relationships of hyperlipidemia,
hypertension, thrombosis, diabetes, smoking, and other systemic risk
factors to the etiology and pathogenesis of atherosclerosis.  The SCORs
have advanced our understanding of the structure and function of
lipoproteins and apolipoproteins at the systemic and cellular levels
and their role in atherogenesis.  The program contributed greatly to
the development of the concept of the oxidative modification hypothesis
for atherosclerosis, and demonstrated that cholesterol lowering in
Familial Hypercholesterolemia retarded the progression and promoted the
regression of human coronary atherosclerotic lesions.  The SCORs
pioneered research on nutrition, lesion dynamics, and the relationship
of hemodynamics to atherogenesis, and led to the establishment of
nonhuman primate resources.  The SCORs made important contributions to
the pediatric aspects of atherosclerosis, and conducted behavioral and
psychosocial research, and demonstration and education projects.  Many
of these studies have advanced sufficiently so as to no longer warrant
a "special" program and are now supported by other mechanisms.

Despite the significant progress achieved, however, there remain many
unresolved questions in atherosclerosis research that are well suited
for the comprehensive and multidisciplinary nature of the SCOR
mechanism.  The past accomplishments of the SCOR/A program and the
potential for continued advances in understanding and averting
atherosclerosis and coronary artery disease through an integrated
program of clinical and basic research are the basis for continuation
of this avenue of support.

Atherosclerosis research is evolving; a shift of emphasis has gradually
occurred from a predominant interest in the role of lipids and
lipoproteins, towards defining the role of the arterial wall and its
interactions with systemic factors.  This shift has led to a change in
the direction of the current solicitation.

Significant progress has been made in elucidating the structure and
function of lipoproteins and apoproteins, the generation of useful
animal models for nutrition and metabolic studies, and the definition
of factors influencing localization of atherosclerotic lesions.  Other
ongoing activities over the last decade have considerably expanded
insight into relevant processes in the arterial wall.  An explicit
pathogenesis is emerging and the development of new modes of
intervention to show the progression of the disease is now possible.
However, much of the pathobiology involving the arterial wall is
incompletely defined, and this is believed to be especially important
in the clinical expression of atherosclerosis.

Critical Areas of Research Opportunity

To optimize the impact of the new SCOR program in the next decade,
emphasis needs to be placed on the pathobiology of the arterial wall
that results in the initiation, progression, complication, and
regression of atherosclerosis.  Studies on systemic factors promoting
atherogenesis and its complications acting at the level of the vessel
wall also need to be addressed.  To delineate the mechanisms
responsible for atherosclerosis and its complications in humans,
sophisticated, state-of-the-art methodologies and approaches of
molecular medicine such as gene regulation, gene transfer,
three-dimensional structural biology, vascular imaging techniques, gene
mapping and identification, and genetically modified animal models are
required, as well as the more standard research approaches.

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,
genetically altered animals, and the like), will be established to
prevent duplication of efforts and to maximize benefits in the most
cost-efficient manner possible.

The following are examples of methods, approaches, and areas of
opportunities for research into lesion susceptibility and initiation;
progression, complication, and regression of atherosclerotic lesions;
and systemic factors promoting atherogenesis and its complications
acting at the level of the arterial wall.  The list is not to be
regarded as complete or exclusive and other research proposed by
applicants that meet the objectives of this program will be considered
by the NHLBI.  It includes examples of several questions pertaining to
blacks.

Mechanisms Involved in Lesion Susceptibility and Initiation

Hemodynamic factors influence the localization of the atherosclerotic
lesion.  The role of sheer stress in affecting the site of early
lesions is controversial in view of the demonstrated existence of
selective ion channels that may signal changes in the local hemodynamic
environment in vascular cells.  In addition, there exists a newly
discovered Shear Stress Response Element and DNA binding proteins in
the promoter regions of certain genes that encode growth factors or
adhesion molecules that are thought to play a role in lesion
initiation.  This type of work provides a framework for novel molecular
approaches to the study of atherosclerotic lesion initiation that
promise to provide insight into the critical links among well-defined
risk factors, hemodynamics, and locally altered arterial wall biology.
Another important gap in our knowledge of lesion initiation in humans
relates to the formation of the arterial intima and the heterogeneity
of smooth muscle and endothelial cells in the human arterial wall.  New
concepts of vascular developmental biology and molecular tools for
distinguishing subpopulations of arterial cells are currently emerging.
An opportunity thus exists to approach key issues in the initiation of
human atherogenesis that previously have remained elusive.

The effects of the well established risk factors on CHD events in the
population at large have been shown to apply also to blacks, and most
studies show that hypertension, glucose intolerance, and obesity may
contribute disproportionately to CHD in black populations.  The
contribution of these risk factors to lesion initiation and
acceleration would shed light on devising approaches for interventions
targeted to black populations.

Mechanisms Involved in Lesion Progression, Complication, and Regression

Recent clinical and pathological data show that, in human coronary
atherosclerosis, rupture of the plaque, rather than gradual closure,
underlies many acute myocardial infarctions and episodes of unstable
angina, and that non-occlusive plaque rupture may constitute an
important mode of episodic lesion progression.

Arterial calcification is a prominent feature of coronary
atherosclerosis and correlates with increased risk of myocardial
infarction and may play an important role in plaque rupture.
Calcification of the arterial wall has been shown to result from the
expression of the same genes that are involved in bone formation.  When
calcium and vitamin D are prescribed to prevent osteoporosis, the
potential for enhancing arterial calcification exists.  Further
research into the molecular mechanisms of arterial calcification may
yield new insights into the aging of the vasculature and present new
targets for clinical intervention.

Normal hemostasis and vascular patency are maintained by a dynamic
equilibrium between the fibrinolytic and coagulation systems.
Endothelial cells play a central role in hemostatic regulation by
producing components of the coagulation and the fibrinolytic systems
and inhibitors of platelet aggregation.  Hence, several issues
implicating the hemostatic system in atherogenesis merit consideration.
These may include interactions of the coagulation factors with blood
lipids and their impact on the function of the endothelial cells and
blood cells; mechanisms regulating the interaction of the blood
components with the vascular endothelium in thrombosis and
atherogenesis; factors regulating endothelial functions such as
macromolecular transport, abnormal permeability, and endothelial cell
relaxing factor; and mechanisms controlling arterial endothelial
thrombo-resistance processes.

Potential specific areas of new research might include studies of
apoptosis of cells within plaques, matrix accretion and dissolution,
studies on the origin of the calcifying cells of the arterial wall,
regulation of prothrombotic factors such as tissue factor within
complex lesions, and formation of plaques in microvessels which are
sources of intraplaque hemorrhage.

Emerging vascular imaging modalities provide a major opportunity to
probe, in vivo, the nontraditional mechanisms of plaque progression and
complication.  Human tissue, such as that obtained at atherectomy from
black and white male and female patients, can be utilized to shed light
on the alterations in cellular and molecular regulatory mechanisms, as
well as on possible differences among races.  The use of these
technologies may provide information on the structure of the intima,
media, and adventitia of coronary arteries, which may elaborate on the
vascular remodeling and compensatory responses to atheroma.  Such
observations may provide insight into how profiles of risk factors in
blacks and whites influence these pathophysiological mechanisms.

Plaque rupture and acute thrombosis have been identified as major
substrates for acute coronary syndromes in the general population.
However, it is not known whether current concepts about lipid content
and structure of the fibrous cap of atheroma are directly applicable to
blacks, or whether these characteristics have a more pronounced
influence on the development of acute coronary syndromes owing to the
high prevalence of hypertension, thrombotic diathesis and high levels
of lipoprotein (a) [Lp(a)] in blacks.

As stenotic but stable plaques seldom cause lethal clinical
manifestations, a biological approach to understanding the mechanisms
of plaque destabilization should suggest novel therapies aimed at
reversing this process, a target newly envisioned in cardiovascular
therapeutics.  One potential avenue to this end could involve local
gene therapy using newly developed vectors and endovascular delivery
systems.

Systemic Factors Promoting Atherogenesis and its Complications Acting
at the Level of the Arterial Wall

Many systemic factors associated with atherosclerosis have been
identified.  However, understanding how these risk factors interact
with vascular cells has lagged.  One high priority area in this regard
involves the complex interactions of insulin resistance, dyslipidemia,
hypertension, and central obesity with coronary heart disease.  These
risk factors are particularly prevalent in the black population where
studies of these complex interactions and their association with race
would be desirable.  The advent of genetically altered animals such as
mice provides a new avenue to explore the integrative metabolic and
local arterial wall aspects of such systemic factors that promote
atherogenesis.

For example, an area of interest that could be used to probe the link
of systemic factors with atherosclerotic lesions would be the
generation of compound mutants of insulin-resistant mice with apo-E- or
LDL receptor-deficient animals on different diets.  Once established,
such newly created animal models could be used for systematic
evaluation of the effect of dietary and other environmental variables
on atherogenesis.  Likewise, such compound mutant animal strains could
be used to test potential preventive and therapeutic measures.  Various
compound mutant animals could be applied to advantage to probe
polygenic risk factors that promote atherogenesis (e.g., crosses with
animals over-expressing or with gene knockouts involving growth
factors, cytokines, coagulation factors, and apolipoproteins).

Molecular Medicine Methods and Approaches

Responses to this RFA should apply modern methods and approaches of
molecular medicine to studies of the pathogenesis of atherosclerosis in
the arterial wall and should emphasize the molecular and cellular bases
of atherogenesis and the molecular genetics of atherosclerosis. The
methodology to be used may include, among others, the following
approaches:

Genetics/Gene Manipulation

The power to map and identify genes responsible for disease, the
capability of delivering exogenous genes to cells and organs, and the
ability to manipulate gene expression and regulation all provide
opportunities to investigate the role of various factors on vessel wall
biology.  Examples of methods and approaches include:

o  Methods to Prevent Specific Gene Expression (e.g., antisense)
o  Understanding Gene Expression in the Developing Animal.
o  Gene Transfer and Therapy.
o  Generation of Genetically Altered Animals.
o  Gene Mapping and Identification.

Structural Biology

Elucidation of the fine structure of the key enzymes, receptors, growth
factors, cytokines, etc., at the three-dimensional level is an
important step toward understanding their mechanisms of action on the
vessel wall and designing agonists or antagonists to perturb their
activity.  Examples of the methodology to be used include:

o  X-Ray Crystallography
o  NMR
o  New Electron and Laser Microscopy Techniques

Vascular Imaging Techniques

The imaging of arterial lesions can be used to investigate the
pathophysiological basis for the development and progression/
regression of atherosclerosis and to predict the impact of intervention
on progression/ regression.  The use of improved methods for invasive
and noninvasive imaging of lesions, especially plaque rupture and acute
occlusion, is a high priority.  Examples of the methods that can be
used include:

o  Quantitative Angiography
o  B-Mode Ultrasound
o  Intravascular Ultrasound
o  NMR

Basic and Clinical Research

The overall concept of a SCOR program focuses on scientific issues
related to diseases relevant to the mission of the NHLBI.  It is
essential, therefore, that all applications include both basic and
clinical research projects.  In the ideal SCOR, the clinical research
derives from, or is otherwise intimately linked to, the basic research
proposed by the investigators.  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.

Each SCOR grant application and award must include research involving
human/patient subjects.  Support may be provided for human biomedical
and behavior 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.  In addition, basic research projects must be included that
relate to the clinical focus.  A SCOR may also contain one or more core
units that support the research projects.  Special instructions
pertaining to the regulations regarding inclusion of human subjects in
research are detailed under the section STUDY POPULATION.

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 new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43)
and supersedes and strengthens the previous policies (Concerning the
Inclusion of Women in Study Populations, and Concerning the Inclusion
of Minorities in Study Populations), which have been in effect since
1990. The new policy contains some provisions that are substantially
different from the 1990 policies.

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 reprinted
in the NIH Guide for 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.

LETTER OF INTENT

Prospective applicants are asked to submit, by October 9, 1995 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
subsequent applications, the information that it contains is helpful in
planning for the review of applications.

The letter of intent is to be sent to:

Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 553 A
Bethesda, MD  20892-9070

Upon receipt of the letter of intent, applicants will be contacted by
program staff to discuss their proposed applications and to provide
guidance to applicants not familiar with the SCOR concept.

APPLICATION PROCEDURES

The research grant application for PHS 398 (rev. 9/91) is to be used in
applying for these grants.  These forms are available at most
institutional offices of sponsored research and may be obtained from
the Office of Grants Information, Division of Research Grants, National
Institutes of Health, Westwood Building, Room 449, Bethesda, MD
20892-9070, telephone 301/435-0714.

Applicants must follow the instructions provided in the supplement to
the RFA.

Applicants from institutions 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 could be included with the
application.

The RFA label available in the PHS 398 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,
to identify the application as a response to this RFA, check "YES,"
enter the title "Specialized Center of Research in Molecular Medicine
and Atherosclerosis," and the RFA number HL-95-006 on Line 2a of the
face page of the application.

Send or deliver a signed, typewritten original of the application,
including the checklist, and three signed photocopies, in one package
to:

Division of Research Grants
National Institutes of Health
Westwood Building, Room 240
Bethesda, MD  20892-9070**

Send two additional copies of the application to Dr. C. James Scheirer,
Chief, Review Branch, Centers and Special Projects Section at the
address listed under LETTER OF INTENT.  It is important to send these
two copies at the same time as the original and three copies are sent
to the Division of Research Grants, otherwise the NHLBI cannot
guarantee that the application will be reviewed in competition for this
RFA.

Applications must be received by December 8, 1995.  If an application
is received after that date, it will be returned to the applicant.  The
Division of Research Grants (DRG) will not accept any application in
response to this RFA that is essentially the same as one currently
pending initial review, or 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 DRG and
for responsiveness by the NHLBI.  Incomplete applications will be
returned to the applicant without further consideration.  If NHLBI
staff find that the application is not responsive to the RFA, it will
be returned without further consideration.

Applications that are complete and responsible to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
group convened by the NHLBI in accordance with the review criteria
stated below.  As part of the initial merit review, a process (triage)
may be used by the initial review group in which applications will be
determined to be competitive or non-competitive based on their
scientific merit relative to other applications received in response to
the RFA.  Applications judged to be competitive will be discussed and
be assigned a priority score.  Applications determined to be
non-competitive will be withdrawn from further consideration and the
principal investigator/program director and the official signing for
the applicant organization will be notified.  Neither site visits nor
reverse site visits are planned as a part of the review process,
therefore each application should be complete on submission.

Review criteria for RFAs are generally the same as those for
unsolicited interdisciplinary research grant applications.

o  the scientific merit of each proposed project in the application,
including originality, feasibility of the approach, and adequacy of the
experimental design;

o  the integration of the clinical and fundamental research into a
coherent enterprise with adequate plans for interaction and
communication of information and concepts among the collaborating
investigators;

o  the technical merit and justification of each core unit;

o  the qualifications, experience, and commitment of the SCOR Director
and his/her ability to devote adequate time and effort to provide
effective leadership;

o  the competence of the investigators to accomplish the proposed
research goals, their commitment, and the time they will devote to the
program;

o  the adequacy of facilities to perform the proposed research
including the laboratory and clinical facilities, access to subjects,
instrumentation, and data management systems when needed;

o  the scientific and administrative structure of the program,
including adequate internal and external arrangements and procedures
for monitoring and evaluating the proposed research and for providing
ongoing quality control and scientific review;

o  the institutional commitment to the program and the appropriateness
of the institutional resources and policies for the administration of
a research program of the type proposed; and

o  the appropriateness of the budget for the proposed program.

o  Adequacy of plans to include both genders and minorities and their
subgroups as appropriate for the scientific goals of the research.
Plans for the recruitment and retention of subjects will also be
evaluated.

AWARD CRITERIA

Applications must fulfill all eligibility criteria in order to be
considered for funding.  Since a variety of approaches would represent
valid responses to this RFA, it is anticipated that there will be a
range of costs among individual grants awarded.  The most important
criterion in selecting awardees will be the scientific merit as
reflected in the priority score.  However, factors such as program
balance and available funds may enter into selection from among
meritorious applications.

Schedule

Letter of Intent Receipt Date:     October 9, 1995
Application Receipt Date:          December 8, 1995
Review by NHLBI Advisory Council:  September 1996
Anticipated Award Date:            December 1, 1996

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues to:

Dr. Momtaz K. Wassef
Division of Heart and Vascular Diseases
National Heart, Lung, and Blood Institute
Federal Building, Room 4A12
7550 Wisconsin Avenue  MSC 9050
Bethesda, MD  20892-9070
Telephone:  (301) 496-1978
FAX:  (301) 480-9882
Email:  momtaz_wassef%nihhfed1.bitnet@cu.nih.gov

Inquiries regarding fiscal and administrative matters may be directed
to:

Mr. William Darby
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892-9070
Telephone:  (301) 594-7458
FAX:  (301) 594-7492

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance
No. 93.837, Heart and Vascular Diseases.  Awards will be made under the
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 requirement of Executive Order 12372 or Health
Systems Agency review.

.

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