Full Text HL-96-001

SICKLE CELL DISEASE THERAPY

NIH GUIDE, Volume 24, Number 40, November 24, 1995

RFA:  HL-96-001

National Heart, Lung, and Blood Institute

P.T. 34

Keywords: 
  Blood Diseases 
  Biology, Cellular 
  Biology, Molecular 
  Chemotherapeutic Agents 


Letter of Intent Receipt Date:  December 22, 1995
Application Receipt Date:  January 23, 1996

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

PURPOSE

The Division of Blood Diseases and Resources (DBDR) of the National
Heart, Lung, and Blood Institute (NHLBI), National Institutes of
Health (NIH), invites research grant applications for the support of
research leading to the development of effective therapeutic
approaches for the treatment of sickle cell disease.

HEALTHY PEOPLE 2000

The Public Health Service (PHS) is committed to achieving the health
promotion and disease prevention objectives of "Healthy People 2000",
a PHS-led national activity for setting priority areas.  This Request
for Applications (RFA), Sickle Cell Disease Therapy, is related to
the priority areas of chronic disabling conditions, and maternal and
infant health.  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 and 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 unusual merit, need, and promise, and in accordance with
PHS policy governing such awards.  Applications from minority
individuals and women are encouraged.

MECHANISM OF SUPPORT

This RFA will use the NIH individual research project grant (R01)
mechanism of support.  However, specific application instructions
have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME"
streamlining efforts being examined by the NIH.  The modular grant
concept establishes specific modules (increments) 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 NHLBI 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.  A feature of the modular grant concept is that not
escalation is provided for future years, and all anticipated expenses
for all years of the project must be included within the number of
modules being requested.  Only limited budget information will be
required and any budget adjustments recommended 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 are requested to furnish estimates of the time required to
achieve the objectives of the proposed research project.  Up to four
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 awards resulting from RFA HL-96-001
will begin August 1, 1996.  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
RFA, it is anticipated that there will be a range of costs among the
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 1996, $1.2 million total costs
will be available for the first year of support for this initiative.
Award of grants pursuant to this RFA is contingent upon receipt of
such funds for this purpose.  It is anticipated that approximately
four new grants will be awarded under this program.  The specific
number to be funded will, however, depend on the merit and scope of
the applications received and on the availability of funds.  Direct
costs will be awarded in modules of $25,000, less any overlap or
other necessary administrative adjustments.  Indirect costs will be
awarded based on the negotiated rates.  Collaborative arrangements
involving subcontracts with other institutions should be discussed
with Ms. Jane R. Davis at the address listed under INQUIRIES.

RESEARCH OBJECTIVES

Background

Effective therapy remains a primary goal of the Sickle Cell Disease
Program.  Research in recent years has provided significant advances
in the state of knowledge of the pathophysiology, genetic
characteristics, molecular and cellular biology, natural history, and
clinical aspects of the sickling disorders.  Despite this progress,
there is still no universally effective therapeutic agent for this
disease.

The recent results of the Multicenter Study of Hydroxyurea have shown
that hydroxyurea is effective at reducing the complications
associated with severe sickle cell disease in some individuals.
However, it is clear from these studies that not all patients with
sickle cell disease respond to hydroxyurea.  In addition, the long
term side effects of this drug are not known, and the safety and
efficacy of this drug for pediatric patients are not known.  Thus,
other approaches to sickle cell disease therapy that have the
potential to be less toxic and more universally applicable are
needed.  Furthermore, approaches that would enhance the therapeutic
effects of hydroxyurea would also be extremely beneficial.

Research in recent years has led to an increased understanding of the
extraordinarily complex pathophysiological consequences of sickle
cell disease.  The central event involves the deoxygenation-induced
accumulation of hemoglobin S polymers, leading to an increased
intracellular viscosity and the generation of deformed sickled red
cells. However, this does not fully explain sickle disease
pathophysiology, and even the sickling process itself is governed by
various factors.  It is clear that diverse mechanisms contribute to
catastrophic interruptions of microcirculatory flow and consequent
vaso-occlusive manifestations.  Contributory factors include red cell
sickling, red cell adherence to vascular endothelial cells,
abnormalities of the red cell membrane causing cellular dehydration
and poor deformability, and possibly abnormalities of coagulation and
vascular tone.  Likewise, the characteristic hemolytic anemia of
sickle cell disease derives from diverse mechanisms, including red
cell fragility, sequestration, opsonization with immunoglobulin, and
interaction with phagocytic macrophages.  The capacity of some sickle
red cells to adhere to the endothelium or interact with other cell
types leading to the increased production of various cytokines,
peptides or other vaso-active substances may also impact on the
pathology of this disease.

Therapeutic Opportunities

The multifactorial aspect of sickle disease pathophysiology provides
a number of potential opportunities for therapeutic intervention.
Several approaches could be utilized to inhibit the basic sickling
process.  Emphasis in the past was on the identification of molecules
capable of increasing the affinity of hemoglobin S for oxygen, agents
that inhibit polymerization, or molecules that alter the critical
contact points involved in polymer formation (an approach that may
deserve further study).  The detailed data now available regarding
the development and structure of the hemoglobin S polymer may provide
a basis for rational design of inhibitors based on specific binding
to defined regions of the hemoglobin S molecule.  Alternatively,
since sickling depends so strikingly on hemoglobin S concentration,
this process could be inhibited by agents that lower this
concentration, either by direct effects on hemoglobin synthesis or by
increasing cell water content, i.e., correcting cellular dehydration.
Pharmacologic or genetic manipulation can be used to increase
cellular content of fetal hemoglobin, which inhibits the
polymerization process.

The abnormal adherence of sickle red cells to endothelial cells can
delay microvascular transit times and thereby promote sickling, and
adhesion may even directly initiate vaso-occlusion.  Various
therapeutic approaches could be relevant since adherence derives from
several different mechanisms and involves the endothelial cell itself
plus abnormalities of both the red cell membrane and plasma proteins.
Agents that specifically inhibit one or another of the identified
adherence mechanisms warrant further investigation.  Since red cell
subpopulations exhibit differences in adhesiveness, therapeutic
benefit also theoretically could be derived from agents that alter
subpopulation size or composition.

Several approaches could be valuable for dealing with the various
defects of the sickle membrane that lead to abnormal cellular
dehydration, which promotes sickling and has an adverse effect on
deformability.  The calcium-mediated direct loss of cations and water
during red cell sickling could be prevented by specific Gardos
channel inhibitors.  Also of possible value would be agents that
selectively interfere with the K:CL cotransport pathway that is
abnormally active in sickle reticulocytes and that can dehydrate even
oxygenated sickle erythrocytes. Since rapid development of red cell
dehydration tends to be a characteristic of those cells having low
hemoglobin F levels, successful manipulation of cell fetal hemoglobin
content might prove beneficial.  Additionally, it would be reasonable
to examine inhibitors of the deformation-activated potassium leak
pathway that is exaggerated for cells that have minimal amounts of
oxidized membrane lipid, as is the case for sickle red cells.

The disparate abnormalities of sickle red cells suggest other
approaches of potential therapeutic value that include, but are not
limited to, the following:  (1) benefit might derive from agents that
stabilize the sickle membrane or otherwise inhibit the vesiculation
process that contributes procoagulant material to sickle plasma, (2)
vasoactive substances possibly could be utilized to manipulate
vascular tone and flow dynamics, (3) agents that modify or inhibit
formation of the sickle membrane's abnormal stiffness would likely be
useful, and (4) approaches that lessen membrane fragility or prevent
accumulation of opsonizing immunoglobulin on the cell surface might
be of value in diminishing the severity of anemia.

There is also continued interest in cell-cycle specific agents, such
as 5-azacytidine and hydroxyurea that turn on the expression of the
fetal hemoglobin gene.  These compounds have demonstrated the
capability of generating increased synthesis of Hb F in red cells of
animals and patients, but serious concerns exist regarding the
toxicity of 5-azacytidine.  Hydroxyurea, which is much safer, has now
been used in a small number of patients with reports of significant
elevations of HbF, and a clinical trial has recently revealed that
recurrent painful episodes can be reduced by 50 percent in patients
with severe sickle cell disease.  More recently erythropoietin and
sodium butyrate have been added to the list.  By themselves or in
combination with hydroxyurea, they also increase the synthesis of Hb
F in red cells.  More information about the molecular, genetic, and
cellular basis of action of these agents is needed.  Allogenic bone
marrow transplantation has recently begun to be used for therapy of
this genetic disease but has not yet been widely accepted.  Other
approaches that involve replacing genes in autologous bone marrow
cells using DNA-mediated gene transfer using viral vectors are
underway with the idea of treating genetic diseases, including sickle
cell anemia.  Additional efforts could also be focused on a general
understanding of stem cell biology and erythroid cell
differentiation, with the goal of using targeted peripheral stem-
cells as alternatives or adjuncts to bone marrow
transplantation.

Of equal importance, recent advances in molecular genetics, including
identification of cis-acting DNA sequences and trans-acting proteins,
have clarified the genetic mechanisms controlling the expression of
hemoglobin genes and, in particular, the switches from embryonic and
fetal to adult hemoglobins.  Methods of isolating and growing stem
cells in culture from bone marrow or peripheral blood should also
prove useful in developing genetic approaches to sickle cell disease
treatment.  These studies promise to clarify the mechanisms of action
of drugs like hydroxyurea, butyrate, and erythropoietin which affect
expression of Hb F, and are also  relevant to the long term
development of gene therapy by attempts to transfer genes for normal
hemoglobin or under ideal circumstances to use targeting to replace
the defective sickle gene in stem cells.

Judicious Timing

The extraordinary complexity of sickle disease makes it unlikely that
a complete solution to its pathophysiology will be forthcoming in the
immediate future.  On the other hand, the greater understanding of
this pathophysiology stemming from research over the last decade
identifies a number of areas that might be profitably exploited in
terms of effective therapeutic intervention.  The preceding
discussions do not represent an all-inclusive listing of these
opportunities, but merely indicate the great variety of possibilities
that could be considered given the current state of knowledge and
understanding.

In addition, certain recent developments make this a particularly
opportune moment for considering intervention strategies.  The
creation of transgenic sickle mice provides the opportunity for
animal testing of certain strategies that are best evaluated in vivo.
The establishment of flow models utilizing in situ vascular beds or
endothelialized flow chambers now allows instructive evaluation of
sickle cell adhesiveness under physiologic conditions.  Further
development of micropipette technology and other analytical systems
has allowed more revealing analysis of red cell membrane properties
and recent years have provided a general advancement of knowledge in
areas relevant to sickle disease.  Examples include the biology of
adhesive molecules and their receptors, computer assisted molecular
design, vascular biology/physiology, and the biophysical properties
of membrane proteins and lipids.

In virtually all cases, such advances have been used primarily to
extend our knowledge of the pathophysiology of sickle cell disease.
While the development of therapeutic strategies cannot and should not
be separated from this enhanced understanding, it is clear that the
attainment of our therapeutic goal will be greatly facilitated by
targeting basic and applied research to the specific problem of
identifying mechanisms that will lead to effective therapies. In this
regard, the impressive results of the hydroxyurea clinical trial does
not obviate the need for further studies.  There are clearly
nonresponders and others for whom this chemotherapeutic drug is not a
satisfactory therapy, and the long term side effects of this drug are
currently unknown.  Moreover, since early studies suggest that the
beneficial effects of hydroxyurea may derive from diminution of RBC
adhesiveness and/or improvement of cellular hydration rather than
from effects on hemoglobin F level alone, it is possible that
equivalent benefit could be derived from alterative approaches.  This
approach is worth considering, particularly for sickle children who
may not be candidates for cytotoxic agents. Clearly, the continued
development of rational therapeutic strategies is needed.

With respect to methodology, it may be noted that the classic cell
sickling assays have been complemented and in some ways supplanted by
assays of the thermodynamics and kinetics of deoxyhemoglobin S
gelation in solution, the intracellular polymerization of
deoxyhemoglobin S, and the oxygen affinity of concentrated solutions
of Hb S and sickle erythrocytes.  These advances in assay techniques
increase the opportunity to conduct more basic research in the area
of the development of therapeutic approaches and have begun to allow
the development of a quantitative approach to evaluating disease
severity.

Recent advances in genetics, cell biology, biophysics, and
biochemistry broaden the search for therapeutic approaches to include
pharmacological manipulation of hemoglobin switching and gene
therapy, as well as strategies designed to develop inhibitors of
polymerization, effectors of red cell volume, and a variety of
physiological and cellular approaches.  This initiative is not
intended to support clinical trials. Rather, it is intended to
support laboratory testing of defined potential therapeutic
approaches based upon our current understanding of sickle cell
disease pathophysiology. The multifactorial aspect of sickle disease
pathophysiology provides a number of potential approaches for
therapeutic intervention.  These approaches include, but are not
limited to:  (1) identification of molecules that are capable of
inhibiting sickle polymer formation, (2) decreasing the intracellular
concentration of Hb S either by a direct effect on hemoglobin
synthesis or by increasing the water content of the cell, (3)
pharmacologic or genetic manipulation to increase the synthesis of
fetal hemoglobin, (4) development of mechanisms that would e red cell
adherence to vascular endothelium, (5) development of agents that
stabilize the membranes of sickle red blood cells, (6) development of
vasoactive substances to manipulate vascular tone and flow
characteristics, or (7) development of agents that modify or inhibit
formation of the sickle membrane's abnormal stiffness.  These
suggested approaches are intended as examples only.  Investigators
are encouraged to consider other innovative approaches.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI will sponsor annual
meetings to encourage the exchange of information among investigators
who participate in this program.  In the budget section of the grant
application, applicants must include one meeting each year to be held
in Bethesda, Maryland.  Applicants should also include a statement in
the application 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 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 new
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 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 December 22, 1995, a
letter of intent that includes a descriptive title of the proposed
research and identification of any other participating institutions.
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 necessary to have sent
a letter of intent to submit an application.  The letter of intent is
to be sent to:

Chief, Review Branch
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

APPLICATION PROCEDURES

Applications are to be submitted on the research grant application
form PHS 398 (rev. 5/95).  This form is available in an applicant
institution's office of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health,  6701 Rockledge Drive, Room 3034 - MSC 7762, Bethesda, MD
20892-7762 telephone (301) 435-0714, email: girg@drgpo.drg.nih.gov.

This RFA uses the "Just-in-Time" concept.  The following
modifications must be made to the standard PHS 398 application
instructions:

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

o  INITIAL BUDGET PERIOD - Only the names of personnel and level of
effort must be itemized in the Personnel section of the "Detailed
Budget for the Initial Budget Period" (Form Page 4).  In addition,
list consultants, equipment, supplies, travel, patient care
activities, alterations and renovations, and other needs, as
appropriate.  Costs are not to be indicated for these individual
items or categories.  If subcontracts are involved, state the name(s)
of collaborating institutions in the "Consortium/Contractual Costs"
section and provide individual budgets as detailed in the
"SUBCONTRACTS" section below.  The "Total Direct Costs" line at the
bottom of the page 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.  Any large one-time purchases, such
as large equipment requests, must be accommodated within these
limits.

o  FUTURE BUDGET PERIODS - It is anticipated that direct cost budgets
will remain the same for each year of the period of award (i.e., the
same number of modules requested for each and every budget period).
Any necessary escalation must 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,
appropriate justification must be provided.  The "Budget for Entire
Proposed Project Period" (top section of Form Page 5) must include
Total Direct Costs requested for each year and the Total Direct Costs
for the Entire Proposed Project Period.  The Justification section
must be completed based on instructions provided on Form Page 5.

o  SUBCONTRACTS - 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 agreement from each
collaborating institution must be submitted with the application.
Initial and future year budgets for subcontracts must be prepared
using the same guidelines as for the main grant except that total
subcontract costs need not be in $25,000 modules.  Requested amounts
must be based on individual needs of the subcontract and must reflect
both direct and indirect costs.  The subcontract costs are included
in the total budget request, which must conform with the number of
$25,000 modules requested.

o  BIOGRAPHICAL SKETCH - In addition to the standard information
requested on Form Page 6, the applicant has the option of providing
the title and source of any sponsored support relevant to the
proposed research.

o  OTHER SUPPORT - No other support information is required on "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.

o  The applicant must 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.

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.

To identify the application as a response to this RFA, check "YES" on
Item 2 of page 1 of the application and enter the title and RFA
number.

SICKLE CELL DISEASE THERAPY:  NHLBI RFA HL-96-001

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.

Send or deliver the completed application and three signed, exact
photocopies to:

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 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 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 January 23, 1996.  If an application
is received after that date, it will be returned to the applicant
without review.  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, unless the
applicant withdraws the pending application.  The 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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NHLBI.  Incomplete applications will be
returned to the applicant without further consideration.  If NHLBI
staff determine 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.  Applications that are complete and responsive
to the program announcement will be evaluated for scientific and
technical merit by an appropriate peer review group convened in
accordance with the standard NIH peer review procedures.  As part of
the initial merit review, all applications will receive a written
critique and undergo a process in which only those applications
deemed to have the highest scientific merit, generally the top half
of applications under review, will be discussed, assigned a priority
score, and receive a second level review by the appropriate national
advisory council or board.

Applications should be prepared so that they can be reviewed without
the necessity of interaction between the applicants and the
reviewers, since no site visit or reverse site visit will be part of
the technical review.

The personnel category will be reviewed for appropriate staffing
based on the requested percent effort and any changes requested in
future years.  The total budget request will be reviewed for
consistency with the proposed methods and specific aims.  The
duration of support will be reviewed to determine if it is
appropriate to ensure successful completion of the recommended scope
of the project.

Review Criteria

o  scientific, technical, or medical significance and originality of
proposed research;

o  appropriateness and adequacy of the experimental approach and
methodology proposed to carry out the research;

o  qualifications and research experience of the Principal
Investigator and staff, particularly, but not exclusively, in the
area of the proposed research;

o  availability of the resources necessary to perform the research;

o  appropriateness of the budget and duration in relation to the
proposed research;

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.

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

AWARD CRITERIA

The anticipated date of award is August 1, 1996.

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 unusual merit, need, and promise, and in
accordance with PHS policy governing such awards.

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. Junius G. Adams, III
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7950
Bethesda, MD  20892-7950
Telephone:  (301) 435-0055
FAX:  (301) 480-0868
Email:  ja33m@nih.gov

Inquiries regarding fiscal matters or collaborative arrangements
involving subcontracts with other institutions may be directed to:

Ms. Jane R. Davis
Blood Division Grants Management Section
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0166

AUTHORITY AND REGULATIONS

The programs of the Division of Blood Diseases and Resources, NHLBI,
are described in the Catalog of Federal Domestic Assistance No.
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.

.

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