SPECIALIZED CENTERS OF RESEARCH (SCOR) IN HEMATOPOIETIC STEM CELL BIOLOGY

Release Date:  August 16, 1999

RFA:  HL-99-021

National Heart, Lung, and Blood Institute

Letter of Intent Receipt Date:  December 1, 1999
Application Receipt Date:  January 14, 2000

PURPOSE

This solicitation invites grant applications to enter a single open
competition for Specialized Centers of Research (SCOR) in Hematopoietic Stem
Cell Biology.  The goal of this initiative is to advance our knowledge of
basic stem cell biology in areas of stem cell isolation, quantitation by in
vivo assay, in vitro and in vivo growth and expansion, gene insertion and
expression, and engraftment.  This basic knowledge will be applied clinically
to enhance our ability to achieve successful hematopoietic stem cell therapy
to cure both genetic and acquired diseases and to perform successful gene
therapy using the hematopoietic stem cell as the target for gene transfection
and for life-long expression of normal genes.

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 initiative, Specialized Centers of
Research (SCOR) in Hematopoietic Stem Cell Biology, is related to the priority
areas of maternal and infant health, and cancer.  Potential applicants may
obtain a copy of "Healthy People 2000," (Full Report: Stock No. 017-001-00474-
0 or Summary Report: Stock No. 017-001-00473-01) through the Superintendent of
Documents, Government Printing Office, Washington, DC 20402-9325 (telephone
202-512-1800).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic for-profit and non-profit
institutions, public and private, such as universities, colleges, hospitals,
and laboratories.  This RFA is intended to support SCOR grants for basic and
clinical investigations.  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.  Foreign institutions are
ineligible from receiving awards under this solicitation.

Under exceptional circumstances, a foreign component critical to a project may
be included as a part of that project.  Women and minority investigators are
encouraged to apply as Principal Investigators or responsible project
investigators.

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 determined
non-competitive, the over all 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.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) specialized centers
(P50) mechanism to support this research program. Responsibility for planning
the proposed project will be solely that of the applicant.  The total project
period for applications submitted in response to the present RFA may not
exceed five years.  The anticipated start date of award is September 30, 2000.

Although multidisciplinary approaches are required, it is not the intent of
this RFA to solicit applications for large clinical trials or large
epidemiologic studies.  In general, funds will not be provided for the
purchase and installation of expensive, new equipment.

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 2001, 2003, and 2005 of the budget.  Applicants should also
include a statement in their applications indicating their willingness to
participate in these meetings.

Basic and Clinical Research

The overall concept of a SCOR program focuses on scientific issues related to
diseases relevant to the mission of the National Heart, Lung, and Blood,
Institute (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 described.

Each SCOR grant application and award must include research involving human
patients/subjects, which is defined as research conducted with human
patients/subjects or on material of human origin such as tissue or other
specimens for which an investigator directly interacts with 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 epidemiologic 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.

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.

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 10 years of support, unless the SCOR program is
recommended for extension.

The SCOR program in Hematopoietic Stem Cell Biology is in the initial
five-year project period and this competition is for the second five-year
competition.  The comprehensive evaluation of this SCOR Program will be
conducted during the second project period according to the following
timetable.

Announcement of SCOR renewal competition   FY 1999
Project Period (second competition)        FY 2000 to FY 2004
Letters to SCOR Directors regarding        FY 2001 (mid-way through year 02
 SCOR evaluation plans                      of the 2nd project period)
SCOR Evaluation Meeting                    FY 2001 (late in year 02 of 2nd
                                            project period)
Notification of SCOR Directors of          FY 2002 (mid-way through year 03
NHLBI decision                              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 and can
provide scientific expertise in areas and topics that may not be readily
available at the applicant institution.  However, the consortium projects must
not constitute greater than 50 percent of the proposed projects.  It is also
imperative that a consortium application be prepared so that the programmatic,
fiscal, and administrative considerations are explained fully. 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.
Facilities and Administrative costs paid as part of a consortium agreement are
excluded from the limit on the amount of direct costs that can be requested. 
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 Operation Branch, NHLBI, (301) 435-0166.

FUNDS AVAILABLE

Applicants may request up to $1,220,000 in direct costs, not including
Facilities and Administrative costs for collaborating institutions, in the
first year.  Competing renewal applicants may request an increase in their
budget in the first competing year (Year 06), not to exceed 10 percent of the
costs awarded in the last noncompeting award year (Year 05) or $1,220,000,
whichever is greater (excluding Facilities and Administrative costs on
subcontracts).  Applicants may request up to a three percent increase for
subsequent noncompeting years.  The specific number to be funded will,
however, depend on the merit and scope of the applications received and on the
availability of funds.

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

The production of blood cells, or hematopoiesis, takes place in the bone
marrow.  Among the billions of cells in the bone marrow, there is a very small
subpopulation that has a pivotal role in the maintenance of hematopoiesis. 
This subpopulation is composed of hematopoietic stem cells (HSC) that, with
their distinctive capabilities of self-renewal and differentiation, furnish a
constant supply of blood cells of all hematopoietic lineages throughout life. 
Thus, the stem cell can either replicate and remain a stem cell or
differentiate into myeloid or lymphoid stem cells, which in turn can further
proliferate and mature, ultimately giving rise to all the circulating blood
cells. Each of these complex  hematopoietic pathways is under the influence of
one or more hematopoietic growth factors or other cytokines that enhance
cellular proliferation and maturation, as well as inhibitory activities which
prevent proliferation.  These activities are generated and act within the
marrow microenvironment.

Currently, allogeneic bone marrow transplants are recognized as a treatment of
choice for chronic myelogenous leukemia, acute leukemias failing initial
treatment, aplastic anemia, and several lethal disorders of the immune system
and of hematopoiesis.  Allogeneic bone marrow transplantation has become
increasingly used as a cure for a variety of genetic defects of the
hematopoietic and immune systems, and for lipid storage diseases.  Genetic
diseases that have been successfully cured by bone marrow transplantation
include Cooley's anemia, sickle cell anemia, severe combined immunodeficiency,
Wiskott-Aldrich syndrome, Fanconi anemia, Blackfan-Diamond anemia, ataxia
telangiectasia, infantile agranulocytosis, Chediak-Higashi disease, chronic
mucocutaneous candidiasis, mucopolysaccharidosis, cartilage-hair hypoplasia,
Gaucher's and other lipid storage diseases.  Some of these diseases, such as
Cooley's anemia (beta-thalassemia) and sickle cell anemia, are major worldwide
public health problems.  Others are devastating orphan diseases that are
extremely costly to treat.  Collectively, these genetic diseases occur in
tens-of-thousands of births per year.

It is also recognized that several malignant disorders are sensitive to agents
which have, as their dose-limiting toxicity, myelo-ablation.  This knowledge,
along with the initial success of marrow and peripheral blood-derived
autografts administered after myelo-ablative therapy, have clearly defined the
rationale for the use of hematopoietic stem and progenitor cells in the
treatment of several non-hematopoietic malignancies, including breast cancer,
which occurs with alarming frequency.

Stem cell transplantation (SCT) has achieved significant therapeutic success
over the last 10 years, providing a viable treatment option for many
previously incurable diseases.  However, several inherent limitations of the
procedure have restricted its widespread use. These include: lack of
sufficient donors for all recipients, a period of bone marrow (BM) aplasia
leading to severe, prolonged neutropenia and thrombocytopenia, and the
potential for tumor contamination in autologous SCT.  Continued research
efforts to address these limitation are needed.  Recent studies suggest that
cord blood transplantation may help eliminate the issue of donor availability
and some post-transplant complications (1).

Recent Advances in Basic/Clinical Science

STEM CELL IDENTIFICATION AND EXPANSION

Considerable progress has been made in purifying primitive cell populations by
cell sorting based on the absence or presence of cell-surface markers (2). 
Characterization of specific sorted fractions for stem-cell function is
currently based on CD34, a cell-surface sialomucin-like adhesion molecule that
is expressed on 1-3 percent of bone marrow cells.  CD34 is not unique to stem
cells, as it is also detected on clonogenic  progenitors and some lineage
committed cells (3).  CD34 has been used as a convenient positive selection
marker to enrich  HSC used in stem cell transplantation and gene therapy. 
However, new  findings  (4) have added to the growing evidence (5,6) that some
stem cells in the bone marrow do not express CD34. The importance of CD34-
negative HSC for human stem cell transplantation is currently unclear.  The
identification of a marker for positive selection of  CD34-negative HSC will
allow further characterization and quantitative analysis by comparison of the
in vivo long-term marrow repopulating ability of CD34-positive and CD34-
negative cells.  Clearly, the most appropriate cell population for
transplantation is an extremely important issue.  Research efforts to
extensively characterize the human HSC and to clarify the significance of the
CD34-negative cell population are important to pursue.

Identification of conditions for optimizing the expansion of different subsets
of primitive cells from various sources has important implications for
clinical transplantation and gene transfer. Currently, this novel domain of
cellular therapy aims to generate stem and progenitor cells, as well as more
differentiated post-progenitor cells and antigen-presenting dendritic cells. 
Recently, a number of laboratories have shown that both early and delayed
phases of engraftment are mediated by PHSC within a graft and that engraftment
can be accelerated by transplanting greater numbers of PHSC.  Thus, increasing
efforts have been directed,  towards developing methods to expand PHSC ex
vivo. The clinical usefulness of ex vivo generated cells needs to be
established.  Identification of the Refinement of cell-based culture systems
and elucidation of the molecular events which permit the  ex vivo expansion of
hematopoietic stem and progenitor cells from various sources is extremely
important to pursue.

STEM CELL MICROENVIRONMENT

The complex processes of erythropoiesis, myelopoiesis, megakaryopoiesis, and
lymphopoiesis are regulated both positively and negatively by the bone marrow
microenvironment.  The bone marrow stromal microenvironment, itself a
connective tissue, is composed of adipocytes, macrophages, endothelial cells,
and mesenchymal progenitor cells.  The stromal cells appear to be derived from
a pluripotent cell located in the marrow, often referred to as a mesenchymal
progenitor cell, which is believed to be distinct from the hematopoietic stem
cell.  Recent laboratory-based evidence now suggests that the combination of
hematopoietic stem cells and bone marrow stromal cells may be required for
maximal engraftment and self renewal of transplanted cells.  In addition,
preliminary data suggest that marrow stromal cells modulate graft-vs-host-
disease (GVHD).  Thus, there is a particular concentrated effort needed for
new strategies to optimize stem cell engraftment.  It is important to assess
the use of mesenchymal cells (1) to enhance engraftment rate and quality after
transplant, (2) to serve as vehicles for delivery of exogenous gene products,
(3) to provide repair of mesenchymal origin tissues, and (4) to facilitate
prevention and treatment of GVHD.  A combined stem and stromal cell strategy
will potentially maximize engraftment and vastly improve therapeutic outcomes.

GENE THERAPY

The success of whole marrow transplantation for the correction of several
genetic disorders has focused attention on the hematopoietic stem cell as a
target for gene therapy for the correction of several genetic disorders of
hematopoiesis and metabolism.  Precisely how to manipulate the stem cell to
achieve efficient gene transfer without compromising the functional potential
required for long-term hematopoiesis remains a critical area of research. 
Studies have demonstrated that retroviral-mediated gene transfer into HSCs is
feasible and safe.  However, currently available HSC gene-transfer protocols
do not reliably transfer genes into HSCs with long-term repopulating capacity. 
A greater understanding of the basic biology of retroviruses and hematopoiesis
will enhance the development of more advanced and efficient HSC retroviral
vector delivery systems.  Successful HSC gene transfer approaches will need to
develop methods of targeting nondividing HSCs and/or stimulating HSCs to
proliferate prior to transduction. New generation of vectors may permit the
inclusion of larger genes, transcriptional regulatory units, tissue specific
expression, and multiple genes and allow the insertion of viral genes into
site-specific genomic locations.

Recent success in the use of gene therapy for the treatment of AIDS and
hemophilia B has been reported.  Dowdy and colleagues (7) report the use of
gene therapy to kill HIV as a potential alternative to highly active
antiretroviral therapy (HAART).  In addition, encouraging progress in the
treatment of hemophilia B with gene therapy was recently demonstrated.  High
and colleagues (8) have developed an adeno-associated viral (AAV) vector that
is able to deliver the canine factor IX gene to hemophiliac dogs.  the
researchers recorded a constant, but low level production of factor IX in the
dogs for 16 months.  Consistent with these results, Kay and colleagues (9)
have developed a similar vector that they injected into the portal vein of the
liver in hemophiliac dogs and recorded factor IX  production for eight months.
The ability to treat hemophiliac animals is a major step forward towards human
clinical trials.  These results support the potential use of this approach for
correction of a variety of genetic disorders, such as thalassemia, Fanconi
anemia, sickle cell anemia, lethal genetic disorders of immunity, and
potentially severe autoimmune disorders and diseases of metabolism.  Important
research needs exist for improved vector systems and understanding the biology
of hematopoietic stem cell gene transfer to achievement  efficient, stable and
long-term genetic correction of hematopoietic stem and progenitor cells and
their mature progeny.

STEM CELL THERAPY

Research in hematopoietic stem and progenitor cells has brought about a new
and fascinating therapeutic opportunity.  The advances described above should
permit more widespread application of stem cell enriched transplants for
genetic and acquired diseases in both children and adults.  The congenital and
acquired marrow failure and dysfunction syndromes may soon be swiftly and
completely treated by the infusion of autologous stem cells rendered normal by
gene insertion, by homologous replacement with the cloned wild-type allele, or
by the transplantation of foreign normal stem cells rendered compatible by
manipulations of surface antigens.  This exciting prospect, which will
massively reduce the overwhelming cost and inefficient efforts to maintain the
lives of afflicted patients, will finally offer a definitive cure for patients
with rare disorders of marrow function such as those with Fanconi's Anemia, 
Wiskott-Aldrich syndrome, and Kostmann syndrome.  It will also offer real hope
to patients with acquired aplastic anemia and to the large numbers of patients
with various forms of thalassemia and sickle cell anemia who must now struggle
with incomplete therapies.

Proposed Research

The SCOR as a Mechanism for Supporting Stem Cell Biology Research

A spectrum of research, ranging from basic molecular and cellular biology,
through clinical applications of this newly acquired knowledge, is now
feasible.  Stem cell biology research is ideally suited to a multidisciplinary
approach.  The collaboration of molecular and cell biologists, hematologists,
immunologists, transplantation biologists, and clinicians will not only
enhance, but is probably required for, the transfer of landmark advances in
basic research into clinical applications.  The SCOR mechanism may facilitate
the development of skilled multidisciplinary teams.  The SCOR mechanism is
uniquely designed support this spectrum of multidisciplinary basic and
clinical research in a synergistic fashion such that major therapeutic
advances will be realized in the next decade in both gene therapy and stem
cell transplantation.

Examples of Areas to be Addressed by this Initiative:

o  Basic stem and progenitor cell biology, evaluating a variety of sources
including marrow, peripheral blood, cord blood, fetal liver, and embryonic
stem cells.

o  Novel markers for stem cell identification to enhance isolation and 
purification. and ex vivo stem cell expansion from a variety of sources.

o  Refinement of cell-based culture systems and elucidation of the molecular
events which permit ex vivo expansion of hematopoietic stem cells from a
variety of sources.

o  Identification and characterization of functional, molecular regulators of
stem cell self-renewal and commitment.

o  In vivo and in vitro assay systems for human stem cells.

o  Role of growth factors, cytokines, receptors, transmembrane signaling,
marrow stroma and microenvironment, and adhesive proteins in stem cell
interactions and hematopoiesis.

o  Identification and characterization of stromal cells which maximize stem
cell engraftment.

o  Enhancing stem cell engraftment through manipulation of stem and progenitor
cell homing receptors in the marrow stroma and on stem cell surfaces.

o  Stem cell transplantation and expression in animal models.

o  Histocompatibility and allo-interactions, mechanism of induction of
transplant tolerance, minimizing the GVH effect and graft rejection, and
maximizing the graft versus leukemia effect.

o  Stem cell therapy to correct genetic diseases and congenital and acquired
marrow dysfunction.

o  Gene therapy using hematopoietic stem cells as targets for gene insertion
and long term expression of normal genes, using retroviral vectors, adeno-
associated viral vectors, and other sources of gene transduction.

The primary focus of the overall SCOR grant application should be on non-
malignant hematologic diseases.

SPECIAL REQUIREMENTS

Special features of SCOR grants are:

o They provide opportunities for investigators with mutual or complementary
interests to engage in multidisciplinary basic and clinical research in a
synergistic fashion such that major therapeutic advances will be realized.

o  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.

o  Inherent in the SCOR program is a special interaction between the SCOR
director, the grantee institution and the Division of Blood Diseases and
Resources (DBDR).  Upon initiation of the program, DBDR will hold periodic
meetings to encourage exchange of information among investigators who
participate in this program and to stimulate collaboration.  Applicants should
include travel funds for a two-day meeting every other year, most likely to be
held in Bethesda, Maryland.  Applicants should also include a statement in
their applications indicating their willingness to participate in these
meetings.

o  The Division's overall SCOR program and each SCOR grant undergo periodic
evaluation.  The progress reports are prepared for the information of the
National Heart, Lung, and Blood Advisory Council, the Division of Blood
Diseases and Resources staff, and ad hoc members of SCOR evaluation groups.

Requirements of SCOR grants:

o  Research conducted at the individual centers must include both basic and
clinical research to ensure that advances in the basic sciences are translated
rapidly into clinical applications and that clinical needs will provide a
direction for the basic research. Therefore, each SCOR grant application and
award must include one or more research projects involving human
patients/subjects.  The basic research projects should clearly relate to the
disease focus and contribute to elucidation of mechanisms underlying the
disease, or to improved diagnosis or management of the disease.

o  Each component project requires a well-described hypothesis, preliminary
data and a time-table for conducting the proposed investigations.

o  If core facilities are included, the relationship of each component project
to each core should be described.

o  The principal investigator should be an established 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.

o  Project leaders must agree to commit at least 20 percent effort to each
project for which they are responsible.  Investigators with minimal research
experience, but promising credentials, may participate; however, it is
expected that most of the project directors will be investigators with
significant research experience.

o  Each SCOR must have a well-delineated organizational structure and
administrative mechanism that foster interactions between investigators,
accelerate the pace of research, and ensure a productive research effort.

o  If a project director transfers to another institution, support for the
project will normally not be continued as a consortium.

Because of the size and complexity of a SCOR, prospective applicants are urged
to consult with the staff of the Division of Blood Diseases and Resources
early in the preparation of the application (see Inquiries section).

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).

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

INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS

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

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

LETTER OF INTENT

Prospective applicants are asked to submit, by December 1, 1999, 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, it assists the 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:

Dr. C. James Scheirer
Division of Extramural Affairs
National Heart, Lung and Blood Institute
6701 Rockledge Drive, Suite 7216, MSC 7924
Bethesda, MD 20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email: js110j@nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 4/98) is to be used in
applying for these grants.  These forms are available at most institutional
business 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: GrantsInfo@nih.gov, and from the NHLBI program
administrator listed under Inquiries. Specific instructions for preparing a
SCOR application are also available from the program contact listed under
INQUIRIES.

The RFA label included in grant application PHS 398 (rev. 4/98) must be
affixed to the bottom of the face page of the application.  Failure to use
this label could result in delayed processing of the application such that it
may not reach the review committee in time for review.  In addition, the RFA
title, SCOR in Hematopoietic Stem Cell Biology and number, HL-99-021 must be
typed on line 2 of the face page of the application form and the AYES@ box
must be marked.

The RFA label and line 2 of the application should both indicate 
the RFA number.

The sample RFA label available at: 
http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to
allow for this change.  Please note this is in pdf format.

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)

At the time of submission, two additional copies of the application must be
sent to 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 (CSR); otherwise the
NHLBI cannot guarantee that the application will be reviewed in competition
for this RFA.

Applications must be received by January 14, 2000. If an application is
received after that date, it will be returned to the applicant without review. 
The CSR will not accept any application in response to this RFA that is
essentially the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The CSR will not accept any
application that is essentially the same as one already reviewed.  This does
not preclude the submission of substantial revisions of applications already
reviewed, but such applications must include an introduction addressing the
previous critique.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness by CSR and
responsiveness by the NHLBI staff.  Incomplete and/or non-responsive
applications 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.  Applicants
should submit the highest quality applications possible to CSR as no site
visits or reverse site visits will be held.  As part of the initial merit
review, a streamlined process may be used by the initial review group in which
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 of review by the National Heart,
Lung, and Blood Advisory Council.

Review Criteria

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.

o  Appropriateness of the central theme and coordination and interrelation of
the research projects and core units.

AWARD CRITERIA

The anticipated date of award is September 30, 2000 (FY 2000) for the SCORS in
Hematopoietic Stem Cell Biology.  Awards will be made according to priority
score, availability of funds, and programmatic priorities.

INQUIRIES

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 programmatic issues and requests for supplemental
instructions to:

Charles M. Peterson, M.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Suite 10018, MSC 7950
Bethesda, MD  20892-7950
Telephone:  (301) 435-0050
FAX:  (301) 480-0868
Email:  petersoc@nih.gov

Direct inquiries regarding fiscal and administrative matters to:

Ms.Jane Davis
Division of Extramural Affairs
National Heart, Lung and Blood Institute
6701 Rockledge Drive, Suite 7174, MSC 7926
Bethesda, MD 20892-7926
Tel: (301)-435-0166
FAX: (301)-480-3310
Email: davisj@nih.gov

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic Assistance No.
93.839, Blood Diseases and Resources.  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 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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