Full Text HL-94-013


NIH GUIDE, Volume 23, Number 13, April 1, 1994

RFA:  HL-94-013

National Heart, Lung, and Blood Institute



Letter of Intent Receipt Date:  May 31, 1994
Application Receipt Date:  September 15, 1994


The objectives of the Specialized Centers of Research (SCOR) program
in Hemostatic and Thrombotic Diseases are to improve the basic
understanding of the processes involved in hemostasis and thrombosis
and to encourage application of this fundamental knowledge to
clinical situations.  This initiative emphasizes the use of new and
innovative technology to provide better insight and develop treatment
for thrombosis and related cardiovascular disorders, which are the
leading cause of death in the United States.


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), Specialized Centers of Research in Hemostatic
and Thrombotic Diseases, is related to the priority area of blood
diseases and resources.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474 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).


Applications may be submitted by for-profit and non-profit domestic
institutions, public and private, such as universities, colleges,
hospitals, and laboratories.  This RFA is intended to support SCOR
grants for basic and clinical investigations.  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 epidemiologic studies or large clinical
trials will be considered unresponsive to this RFA.  Awards will not
be made to foreign institutions; however, under exceptional
circumstances, a foreign component critical to a project may be
included as part of that project.  Women and minority investigators
are encouraged to apply.


This RFA will use the National Heart, Lung, and Blood Institute
(NHLBI) SCOR (P50) grant to support this research program.
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  All current
policies and requirements that govern the research grant programs of
the NIH will apply to grants awarded under this RFA.

Basic and Clinical Research

The overall concept of a SCOR program focuses on scientific issues
related to diseases and therapies relevant to the mission of the
NHLBI.  It is essential, therefore, that all applications include
both basic and clinical research projects.  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

Each SCOR grant application and award must include research involving
human patients/subjects.  Support may be provided for human
biomedical and behavioral 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

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.  Each project
leader must agree to commit at least 20 percent effort to each
project for which he/she is responsible.

Applications from institutions that have a General Clinical Research
Center (GCRC) funded by the National Center for Research Resources,
NIH may wish to identify the GCRC as a resource for conducting the
proposed research.  If so, a letter of agreement from the GCRC
program director/principal investigator could be included with the

Length of SCOR Programs

Each NHLBI SCOR program is limited to 10 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.

Thus, under this policy, a given SCOR grant is awarded for a
five-year project period following an open competition.  If the one
five-year competing renewal that is permitted is awarded, a total of
no more than 10 years of support is possible, unless the SCOR program
is recommended for extension.

The NHLBI comprehensive evaluation of the Hemostatic and Thrombotic
Diseases SCOR will be conducted during the second project period
according to the following timetable:

Program Announced                         FY 1994

Project Period (First Competition)        FY 1996 to FY 2000

Program Reannounced                       FY 1999

Project Period (Second Competition)       FY 2001 to FY 2005

Letter to SCOR Directors Regarding        FY 2002
SCOR Evaluation
(midway in year 02 of 2nd project period)

SCOR Evaluation Meeting                   FY 2003
(late in year 02 of 2nd project period)

Notification of SCOR Directors            FY 2003
Regarding NHLBI Decision
(midway in year 03 of 2nd project period)

Number of Applications

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 listed under INQUIRIES.


Up to $1,125,000 in 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 additional year may be requested
in each application.  Award of grants pursuant to this RFA is
contingent upon receipt of funds for this purpose.  It is anticipated
that at least two new SCOR grants will be funded.  NHLBI's FY 1996
plans for this initiative include a maximum of $4.4 million.  The
specific amount to be funded will, however, depend on the merit and
scope of the applications received and on the availability of funds.

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 in-depth justification.  Final
decisions will depend on the nature of the justification and the
fiscal situation of the NHLBI.

Consortium Arrangements

If a grant application includes research activities that involve
institutions other than the proposed 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 Ms. Jane Davis, Grants Operations Branch, NHLBI,
301-594-7436.  Applicants of SCOR grants 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 of 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



Nearly 50 percent of mortality in the United States is related to
cardiovascular diseases and amounts to about one million deaths per
year.  Thrombotic events precipitate myocardial infarction, deep vein
thrombosis and pulmonary embolism, and stroke.  Unconstrained
thrombosis is the scourge of the present time.  The cost in lives
lost, morbidity, and lost productivity is enormous.  The economic
cost of cardiovascular diseases was an estimated $151 billion in

In spite of these alarming figures, it is important to note that
there have been significant improvements in the ability to combat
thrombotic disorders and cardiovascular diseases.  The death rates
for coronary heart disease and stroke have declined 50 and 58 percent
respectively during the 20-year period from 1970 to 1990.  Because of
the rapid decline in mortality from heart attack since its peak in
1963, there were 491,000 fewer deaths from this cause in 1990.  This
remarkable improvement would not have been possible without major and
consistent progress in research on thrombosis.  However, the present
risk of thrombosis, heart attack, and stroke remains high and is not
acceptable.  The rapid progress in genetics, molecular biology, and
protein chemistry has opened up frontiers and led to the development
of new tools that provide new opportunities to combat thrombosis and
cardiovascular diseases.  Also, the major research advances made by
investigators in thrombosis have significantly contributed to basic
understandings and clinical developments in other disease areas.

Proposed Research

Although significant progress has been made, there are many
opportunities in hemostasis and thrombosis research and the
application of the results to clinical situations.  The following are
intended to serve only as examples and to emphasize the need for
employing a multidisciplinary research approach to important clinical

o  Risk factors for thrombosis

The pathogenesis of thrombosis is complex and its etiology is likely
to be multi-factorial.  Both hereditary and acquired conditions are
involved; inherited predispositions are more clinically disturbing
because they affect patients at an younger age.  There are a number
of genes - antithrombin, protein C, protein S, fibrinogen - in which
a mutation may be prothrombotic.  However, heterozygosity for a
particular mutant allele can be clinically silent in some individuals
but devastating in others.  These differences could be due to
intergene interactions, i.e., variant alleles of other genes may
exacerbate or reduce the effect of the primary genetic trait.  Since
the gene structure of many candidate proteins involved in hemostasis
and thrombosis are known, it may be possible with improved
technologies to perform multigene analysis and provide a genetic
basis of thrombotic disorders.  Recent reports of resistance to
prolongation in clotting time induced by activated protein C in
majority of thrombophillic patients offer hope of identification of
additional risk factors for thrombosis.  Research on the natural
inhibitors of coagulation/fibrinolysis including the development of
animal models may allow genetic manipulations leading to the
delineation of the role of these proteins in hemostasis and
thrombosis.  These studies may allow determination of the causative
factors, provide an objective definition of thrombosis proneness and
application of preventive approaches.

o  Influence of nutritional elements and environmental factors on
thrombotic disease

There is an emerging consensus that many human diseases are related
to behavior, nutrition and environmental factors.  Increasing
emphasis is being placed on prevention by alterations in lifestyle.
Recent data indicate that certain nutritional elements, such as
vitamin E, wine, garlic, fish oil, may be beneficial in the
prevention of thrombosis.  Once the candidate genes that lead to
proneness to thrombosis have been identified, then the effect of
external factors may be studied.  This area related to prevention
requires further research.

o  Diagnosis, assays, and treatment for venous thrombosis

Two million Americans a year develop deep vein thrombosis and
approximately 50,000 will die.  Venous thromboembolism usually occurs
as a complication of a major illness or major surgical procedure in
hospitalized patients.  There are important issues involving
diagnosis, optimal anticoagulation therapy, laboratory assays, and
efficacy of thrombolytic therapy that need further studies.  The
advent of newer agents, such as low molecular weight heparin and
analogues of hirudin, is likely to require systematic and controlled
studies on their efficacy and standardization.  There is a need for
optimal therapy to prevent extensions of thrombosis at early stages
and restore involved vessels to as normal a state as possible.

o  Regulation of adhesive proteins and processes

A number of processes important in hemostasis and thrombosis are
regulated by adhesive protein ligands and their receptors.  The
adhesion of platelets and other cells to the endothelium, and the
aggregation of platelets to each other are thought to be mediated by
this process.  The role of platelet and endothelial (glyco)proteins
including the selectins and integrins in inflammation, signal
transduction and thrombosis need further study.  A detailed
understanding of the regulation of integrin structure-function,
affinity modulation and the role of other environmental factors are
important, not only to thrombosis/hemostasis, but also to other
biological processes.  It is necessary to develop markers of a
dysfunctional endothelium that may be applicable to in vivo
situations and better understand the leukocyte-endothelial
interactions.  The data generated may provide the foundation for the
development of new antithrombotic and anti-inflammatory agents.

o  Genetic regulation of the synthesis, catabolism, and function of
fibrinolytic proteins

Widespread use of thrombolytic therapy has exposed gaps in the
knowledge of the fibrinolytic system, role of platelets in
thrombolysis, thromboselectivity of the lytic agents, and the
mechanism of reocclusion.  The success rate of thrombolytic therapy
has stubbornly stuck around 70 percent.  There is an opportunity here
for collaborative basic research and clinical investigation.

Structure-function relationships in coagulation and fibrinolytic
proteins, studies of macromolecular assembly in the coagulation and
fibrinolytic systems, the enzymology and kinetic analyses of these
systems, although important and productive, are considered mature and
may be supported by other NHLBI grant mechanisms.  Similarly,
qualitative studies on platelet function, for example by
aggregometry, and classification of patient populations are not
encouraged to form the main themes of SCOR applications.
Quantitative studies that address important questions of platelet
dysfunction in specific patient populations and may also contribute
to the understanding of normal platelet biology may form a component
of the application.  There is a need for further education and
research on the influence of behavior, gender, race, and age in
hemostasis and thrombosis.



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 9, 1994 (FR 59 11146-11151) 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.

(NOTE:  When the proposed study or studies in the RFA or PA involves
a gender specific study or a single or limited number of minority
population groups, this should also be stated to inform potential
applicants and reviewers.)


Prospective applicants are asked to submit, by May 31, 1994, 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.  It 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 sent to:

Chief, Review Branch
Division of Extramural Affairs
National Heart, Lung and Blood Institute
Westwood Building, Room 557A
Bethesda, MD  20892


The research grant application form 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, telephone (301) 435-0714.

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 Centers of
Research in Hemostatic and Thrombotic Diseases," and the RFA number
HL-94-013 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

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

Send two additional copies of the application to the Chief, Review
Branch 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 (DRG), otherwise
the NHLBI cannot guarantee that the application will be reviewed in
competition for this RFA.

Applications must be received by September 15, 1994.  If an
application is received after that date, it will be returned to the
applicant.  DRG will not accept any application in response to this
announcement that is essentially the same as one currently pending
initial review, unless the applicant withdraws the pending
application.  DRG 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.


Upon receipt, applications will be reviewed by National Institutes of
Health (NIH) staff for completeness and responsiveness.  Incomplete
applications or applications deemed not responsive to the RFA will be
returned to the applicant without further consideration.

Those applications that are complete and responsive will be evaluated
for scientific and technical merit by an appropriate peer review
group convened by the NHLBI.  Crucial to the initial scientific
review will be a triage process that will eliminate all applications
that are deemed not scientifically competitive within the goals and
criteria of the RFA from further review.  The second level of review
will be provided by the National Heart, Lung, Blood Advisory Council.

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

Factors to be considered in the evaluation of each application will
be similar to those used in review of traditional research grant
applications and, in addition, will include overall proposed
interactions among basic and clinical research projects.  Major
factors to be considered in the evaluation of applications include:

o  Scientific merit of the proposed basic and clinical research
projects including significance, importance, and appropriateness of
the theme; innovation, originality, and feasibility of the approach;
and adequacy of the experimental design.

o  Leadership, scientific stature, and commitment of the program
director; competence of the investigators to accomplish the proposed
research goals and their time commitment to the program; and the
feasibility and strength of consortium arrangements.

o  Collaborative interaction among basic and clinical research
components, the balance between them, and plans for transfer of
potential findings from basic to clinical studies.

o  Adequacy of the environment for performance of the proposed
research including clinical populations and/or specimens; laboratory
facilities; proposed instrumentation; quality controls;
administrative structure; institutional commitment; and, when needed,
data management systems.

o  Appropriateness of the budget for the proposed program.


Written and telephone inquiries concerning this RFA are encouraged.
The opportunity to clarify any issues or questions from potential
applicants is welcome.

Direct inquiries regarding scientific issues to:

Pankaj Ganguly, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 5C14
Bethesda, MD  20892
Telephone:  (301) 402-2237
FAX:  (301) 496-9940

Direct inquiries regarding fiscal and administrative matters to:

Ms. Jane Davis
Division of Extramural Affairs
National Heart, Lung and Blood Institute
Westwood Building, Room 4A15C
Bethesda, MD  20892
Telephone:  (301) 594-7436
FAX:  (301) 594-7492


This program is described in the Catalog of Federal Domestic
Assistance No. 93.839.  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.  All current policies and requirements
that govern the research grant programs of the NIH will apply to
grants awarded under this RFA.  The Public Health Service (PHS)
strongly encourages all grant recipients to provide a smoke-free
workplace and promote the non-use of all tobacco products.  This is
consistent with the PHS mission to protect and advance the physical
and mental health of the american people.


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