THROMBOCYTOPENIA: PATHOGENESIS AND TREATMENT

NIH GUIDE, Volume 26, Number 37, November 7, 1997

RFA:  HL-98-001

National Heart, Lung, and Blood Institute

P.T.

Letter of Intent Receipt Date:  January 29, 1998
Application Receipt Date:  March 12, 1998

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

PURPOSE

The purpose of this initiative is to improve the understanding of
the pathogenesis of thrombocytopenia in general and HIV-related
thrombocytopenia in particular. The long term goal of the
initiative is to develop better therapeutic approaches for these
conditions.

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, Thrombocytopenia: Pathogenesis and Treatment, is
related to the priority areas of HIV infection, and heart diseases
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 202-512-1800).

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. 
Awards in response to this RFA will be made to foreign institutions
only for research of very unusual merit, need, and promise, and in
accordance with PHS policy governing such awards. Minority
individuals and women are encouraged to apply.

MECHANISM OF SUPPORT

This RFA will use the NIH individual research project grant (R01)
mechanism of support. Newly independent investigators who may wish
to consult with a program representative (see "INQUIRIES" section)
are encouraged to apply.  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 and a maximum of eight modules ($200,000 direct costs) per
year may be requested.  Any necessary escalation 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.

Applicants, who will plan and execute their own research programs,
are requested to furnish their own estimates of the time required
to achieve the objectives of the proposed research project.  Up to
5 years of support may be requested.  At the end of the official
award period, renewal applications may be submitted for peer review
and competition for support through the regular grant program of
the NHLBI.  It is anticipated that support for the present program
will begin September 1998.  Administrative adjustments in project
period or amount of support may be required at the time of the
award.  Since a variety of approaches would represent valid
responses to this announcement, it is anticipated that there will
be a range of costs among individual grants awarded.  All current
policies and requirements that govern the research grant programs
of the NIH will apply to grants awarded in connection with this
RFA.

FUNDS AVAILABLE

It is anticipated that for fiscal year 1998, $2,000,000 total costs
will be available for the first year of support for this
initiative.  The award of grants pursuant to this RFA is contingent
upon receipt of such funds for this purpose.  It is anticipated
that approximately eight new grants will be awarded under this
program.  However, the specific number of awards will depend on the
merit and scope of the applications received and on the
availability of funds.  Applicants may request up to five years of
support.  Direct costs will be awarded in modules of $25,000, less
any overlap or other necessary administrative adjustments. Indirect
costs will be awarded based on the negotiated rates.  If
collaborative arrangements involve subcontracts with other
institutions, Ms. Jane R. Davis of the NHLBI Grants Operations
Branch (telephone: (301-435-0166) should be consulted regarding
procedures to be followed.

RESEARCH OBJECTIVES

Background

Idiopathic (autoimmune) thrombocytopenic purpura (ITP) is a common
disorder of immune regulation.  The prevalence of chronic ITP is
estimated to be 1 in 10,000 and it is seen more commonly in women
than in men in about a 3:1 ratio.  Autoantibodies (7S, IgG) are
usually formed against platelets, and probably megakaryocytes,
leading to the destruction of these cells.  The resultant
thrombocytopenia induces purpura and sometimes hemorrhage.
Thrombocytopenia is frequently seen in individuals infected with
the human immunodeficiency virus (HIV) and appears to be
multifactorial in etiology. The virus may directly infect
megakaryocytes and impair thrombopoiesis.  On the other hand,
numerous studies have clearly demonstrated the presence of
platelet-reactive antibodies.

Two developments make this initiative timely.  Firstly, the
discovery of thrombopoietin (TPO) has dramatically changed our
understanding of thrombopoiesis.  Secondly, there has been
considerable progress in basic immunology and particularly
autoimmunity.  The expert recommendations of immunologists and
hematologists that emerged from a Workshop on Autoimmune
(Idiopathic) Thrombocytopenic Purpura:  Pathogenesis and New
Approaches to Therapy are included in this initiative.

ITP affects children and adults of all ages.  In childhood, ITP is
often preceded by a viral infection or vaccination. The disorder is
usually self-limited, and spontaneous recovery occurs in a few
weeks to several months.  The sex ratio in acute ITP is 1:1. 
However, about 10% of the cases become chronic.  In contrast, the
onset of ITP in adults is often more insidious. Autoantibodies are
usually formed against platelets and megakaryocytes, leading to
phagocytic destruction of these cells.  The resultant
thrombocytopenia induces purpura and hemorrhage if the platelet
count reaches a critical level.  In pregnant women, the antibody
may cross the placenta with resultant neonatal thrombocytopenia
which may have serious consequences. Platelet levels temporarily
rise after corticosteroid therapy, but most patients eventually
undergo splenectomy.  The operation leads to normalization of the
platelet counts in 80% to 90% of younger patients and perhaps 50%
to 60% of patients over the age of 50 years, but relapses sometimes
occur many years later.  Some patients have been followed with
chronic ITP for more than 30 years.  The platelet count in these
patients remains around one-third to one-half of normal value but
may drop precipitously after a viral infection or in reaction to
certain drugs.

Thrombocytopenia is common in patients infected with HIV.  In one
study, 9% of HIV-positive drug abusers and 3% of HIV-positive
homosexuals had platelet counts of lower than 100,000/ul while no
seronegative drug abusers or homosexuals were thrombocytopenic.
Thrombocytopenia in these patients seems to correlate with the CD4
lymphocyte count.  The pathogenesis of thrombocytopenia in HIV-
positive individuals is not well understood.  There is evidence for
both increased platelet destruction and decreased platelet
production, and it is possible that either or both of these
mechanisms may play a role in individual patients.

Several studies have demonstrated the presence of platelet-reactive
autoantibodies on platelets and in plasma of affected individuals. 
While HIV-positive individuals may produce antibodies to platelet
antigens similar to chronic ITP patients, some intriguing
differences between conventional and HIV-associated
thrombocytopenias have been noted.  One group reported that in
thrombocytopenia associated with HIV infection, the autoantibodies
recognize platelet membrane proteins distinct from the glycoprotein
IIb/IIIa complex, the preferred target for antibodies in most cases
of conventional ITP.  Platelet associated IgG and C3 values are
both elevated in thrombocytopenic HIV positive individuals compared
to HIV negative patients.  Circulating immune complexes can be
demonstrated in the serum of most patients with HIV-related
thrombocytopenia and these complexes, when purified, are capable of
binding to platelets.  One group of investigators feels that the
immune complexes are made up of antibodies to HIV proteins and its
anti-idiotype and could not demonstrate the presence of HIV
proteins in the complex.  Others reported that these autoantibodies
recognize epitopes on the HIV proteins p24, GP120 and GP160.  One
group has implicated mixed immune complexes containing antibodies
reactive with platelet GPIIIa and HIV-1 proteins as well as IgM
rheumatoid factor in the pathogenesis of the thrombocytopenia. 
Patients with HIV infection have profound immunodeficiency which
could lead to immunomodulation defects and may lead to the
formation of autoantibodies.  There is also the possibility of
immune thrombocytopenia due to antibodies triggered by drugs used
in their treatment.

Platelets are produced from bone marrow megakaryocytes and arise
from the fragmentation of the cytoplasm.  More than three decades
ago it was reported that a humoral factor present in the plasma of
patients with severe thrombocytopenia increased the platelet count
when injected into animals.  This regulator was named
thrombopoietin.  Thrombopoietin (TPO) was isolated and
characterized about three years ago and significant progress in our
understanding of thrombopoiesis has been made since then.  It is
now clear that TPO is the main regulator of megakaryocyte
development and platelet production.  In spite of this impressive
progress, the synthesis, regulation, and signaling mechanisms of
TPO remain unclear.  Its plasma levels in the normal state and
different thrombocytopenic states, its mode of action, and its
clearance mechanisms need to be defined.  A better understanding of
the cell and molecular biology of TPO could  help to guide its
clinical application for the treatment of thrombocytopenia.

There is also evidence to support reduced platelet production in
HIV-associated thrombocytopenia.  Platelet turnover studies show
decreased production in untreated HIV-positive patients with
thrombocytopenia; platelet production improves when they are
treated with zidovudine. Megakaryocytes are known to express the
CD4 antigen, and megakaryocytes from HIV-infected individuals have
been shown to express viral RNA.  In addition, there is reduced in
vitro growth of hemopoietic progenitor cells from HIV-infected
patients, including CFU-megakaryocytes. Finally, common antigens on
platelets and megakaryocytes have been identified.  It is possible
that antibody-mediated impairment of thrombopoiesis has a role in
ITP.

It is clear that the pathogenesis of thrombocytopenia with or
without associated HIV infection is poorly understood.  The
thrombocytopenia observed may be due to the effect of viral
infection on megakaryocytes and platelets, or the immunodeficient
state may permit the formation of antibodies to platelets.  These
antibodies may be similar to those observed in chronic ITP or may
have distinct properties associated with HIV infection.  Studies
are needed to characterize the basic pathophysiology of the
autoimmune response to platelets in ITP more fully and to apply
this knowledge to improve the diagnosis and treatment of this
condition.

Thrombocytopenia associated with HIV has been treated in various
ways.  There are small studies supporting the use of zidovudine,
prednisone, splenectomy, intravenous gammaglobulin, staphylococcal
protein A column, splenic irradiation, interferon, and anti-Rh(D)
antibody.  There is a need to evaluate these various therapies. 
Autoimmune thrombocytopenia may be considered the prototype of an
autoimmune disease indicated by a humoral response and the findings
of this study could be relevant to a number of other autoimmune
conditions.  A clear intent of this initiative is to attract high
level expertise in the field of autoimmunity to the study of ITP in
general and HIV-thrombocytopenia in particular.

Examples of Research Areas

The following are examples of areas of research related to
thrombocytopenia that may be supported under this program. 
Applicants are encouraged to propose additional areas within the
context of this special initiative.

o  Studies utilizing the modern concepts of immunobiology to
develop a better understanding of the pathogenesis of ITP and HIV
thrombocytopenia, and their treatments.  For example, defining  the
defect in immunoregulation that leads to inappropriate antibody
production, exogenous and endogenous triggers (viruses, drugs,
environment, genetic factors) that precipitate the disease,
identification of biologically relevant platelet component and
specific epitopes, defining the apparent subgroups of ITP e.g.
refractory vs. non-refractory, responders vs non-responders to
splenectomy.

o  Studies in HIV - thrombocytopenia determining the frequency of
true autoantibodies in patients of different causes (e.g. drug
abuse, sexual transmission, etc.), molecular mimicry for anti-
platelet antibody, role of immune complexes, involvement of anti-
idiotype antibodies and the etiology of antibody production.

o  Develop an animal model of ITP to study autoimmune pathogenesis
and the characteristics of the antibodies.

o  Studies evaluating thrombokinetics in thrombocytopenia and
determining how platelet production may be suppressed in some
patients.  These might address the levels and effects of
appropriate growth factors on platelet production, e.g. TPO.

o  Develop more sensitive and specific diagnostic methods to better
characterize the antibodies responsible for platelet destruction
(target epitopes, idiotypic properties, classes and subclasses). 
Can in vitro tests distinguish between acute and chronic forms, HIV
and non-HIV ITP and predict the response to treatment?

o  Study the mechanism of action of IV gamma globulin which may
lead to the development of more specific products for the treatment
of ITP and HIV-thrombocytopenia.  Evaluate or develop, in limited
cooperative studies when necessary,  the best forms of treatment in
HIV or non-HIV thrombocytopenia, especially those who have
exhausted available therapeutic options. Large clinical trials on
thrombocytopenia will not be supported under this initiative.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI may sponsor annual
meetings to encourage the 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 the applications indicating their
willingness to participate in such 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 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 reprinted in the NIH GUIDE FOR GRANTS AND
CONTRACTS of March 18, 1994, Volume 23, Number 11.

Investigators may obtain copies from these sources or from the
program staff or contact person listed under INQUIRIES.  Program
staff may also provide additional relevant information concerning
the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by January 29, 1998, a
letter of intent that includes a descriptive title of the proposed
research, the name, address, and telephone number of the Principal
Investigator, identification of any other key personnel or
participating institutions; and the number and title of the RFA in
response to which the application may be submitted.  Such letters
are requested only for the purpose of providing an indication of
the number and scope of applications to be received; therefore,
their receipt is usually not acknowledged.  A letter of intent is
not binding, and it will not enter into the review of any
application subsequently submitted, nor is it a necessary
requirement for the application.  A faxed letter of intent may be
used in place of a posted one.

This letter of intent is to be sent to:

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

APPLICATION PROCEDURES

Applications are to be submitted on the research grant application
form, PHS 398 (rev. 5/95).  Applications kits are available at most
institutional offices of sponsored research and may be obtained
from the Division of Extramural Outreach and Information Resources,
National Institutes of Health, 6701 Rockledge Drive, MSC 7910,
Bethesda, MD 20892-7910, telephone 301/435-0714, email: 
ASKNIH@od.nih.gov.  Use the conventional format for research grant
applications and ensure that the points identified in the section
on REVIEW CONSIDERATIONS are fulfilled.

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:

o  FACE PAGE
As a reminder, Item 7 should be completed to indicate Modular
Direct Costs requested and Item 8 should reflect Total Costs
(Modular Direct plus F & A costs).

o  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.

o  BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT
Do not complete the categorical budget tables on Form page 5 of the
PHS 398 (rev. 5/95). Only the requested total direct costs line for
each year must be completed based on the number of $25,000 modules
being requested. Applicants may not request a change in the amount
of each module.  A maximum of eight  modules ($200,000) direct
costs per year may be requested and each applicant may request 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.

o  BUDGET JUSTIFICATION
- Budget justifications should be provided under "Justifications"
on Form Page 5 of the PHS 398.
- 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.
- Identify all consultants by name and organizational affiliation
and describe the services to be performed.
- 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.  No
specific costs for items or categories should be shown.

o  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 indirect) 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
$175,000 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 for an award, the applicant will be requested to
identify actual direct and indirect costs for all years of the
consortium.  Please note that total subcontract costs need not be
calculated in $25,000 modules.  However, when subcontract funds are
added to the parent grant budget, the total direct cost amount must
be included in the number of $25,000 modules requested.

o  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.
- Complete the educational block at the top of the form page; -
List current position(s) and those previous positions directly
relevant to the application;
- List selected peer-reviewed publications directly relevant to the
proposed project, with full citation;
- 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.

o  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.

o  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.

Sample budgets and justification page will be provided upon
request.

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

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 kit must be
affixed to the bottom of the face page of the original copy 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 and
number must be typed on line 2a of the face page of the application
form and the YES box must be marked.

Send or deliver the completed application and three signed, exact
photocopies of it to the following, making sure that the original
application with the RFA label attached is on top:

CENTER FOR SCIENTIFIC REVIEW (formerly Division of Research Grants)
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for courier/overnight mail service)

Send an additional two 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 Center for Scientific Review. 
Otherwise the NHLBI cannot guarantee that the application will be
reviewed in competition for this RFA.

Applications must be received by March 12, 1998.  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 the
CSR and responsiveness by the NHLBI.  Incomplete applications will
be returned to the applicant without further consideration.  If
NHLBI staff determines that the application is not responsive to
the RFA, it will be returned to the applicant without further
consideration.

Applications that are complete and responsive to the RFA will be
evaluated for scientific and technical merit by an appropriate peer
review group convened by the NHLBI in accordance with the review
criteria stated below.  As part of the initial merit review, a
process 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.

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?

In addition, the adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific
goals of the research will be reviewed.  Plans for the recruitment
and retention of subjects will also be evaluated.

The initial review group will also examine the provisions for the
protection of human and animal subjects, the safety of the research
environment, and conformance with the NIH Guidelines for the
Inclusion of Women and Minorities as Subjects in Clinical Research.

The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.

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

The anticipated date of award is September, 1998.  Funding
decisions will be made on the basis of scientific and technical
merit as determined by peer review, program needs and balance, and
the availability of funds. Awards in response to this RFA will be
made to foreign institutions only for research of very unusual
merit, need, and promise, and in accordance with PHS policy
governing such awards. Designated funding levels are subject to
change at any time prior to award, due to unforeseen budgetary,
administrative and/or scientific developments.

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.

Inquiries regarding programmatic issues and requests for sample
budget pages may be directed to:

Dr. Pankaj Ganguly
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10176
Bethesda, MD  20892-7950
Telephone:  (301) 435-0070
FAX:  (301) 480-1046
Email:  gangulyp@gwgate.nhlbi.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jane R. Davis
Grants Management Office
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0166
FAX:  (301) 480-3310
Email:  jane_davis@nih.gov

AUTHORITY AND REGULATIONS

The programs of the Division of Blood Diseases and Resources,
NHLBI, are described in the Catalog of Federal Domestic Assistance
number 93.839.  Awards will be made under the authority of the
Public Health Service Act, Section 301 (42 USC 241) and
administered under PHS grant policies and Federal regulations, most
specifically 42 CFR Part 52 and 45 CFR Part 74.  This program is
not subject to the intergovernmental review requirements of
Executive Order 12372, or to 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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