Full Text DK-94-005

BASIC RESEARCH ON HEMATOPOIETIC STEM CELL BIOLOGY

NIH GUIDE, Volume 22, Number 35, October 1, 1993

RFA:  DK-94-005

P.T. 34

Keywords: 
  Biology, Cellular 
  Biology, Molecular 
  Growth Factors 
  Receptors 
  Bioassay 


National Institute of Diabetes and Digestive and Kidney Diseases
National Heart, Lung and Blood Institute

Letter of Intent Receipt Date:  November 18, 1993
Application Receipt Date:  January 18, 1994

PURPOSE

The Division of Kidney, Urologic, and Hematologic Diseases (DKUHD),
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), and the Division of Blood Diseases and Blood Resources
(DBDR), National Heart, Lung, and Blood Institute (NHLBI) are
soliciting grant applications for support of basic research focused
on the biology of hematopoietic stem cells.

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), Basic Research on Hematopoietic Stem Cell
Biology, is related to the priority area of diabetes and chronic
disabling conditions.  Potential applicants may obtain a copy of
"Healthy People 2000" (Full Report:  Stock No. 017-001-00474-0) or
"Healthy People 2000" (Summary Report:  Stock No. 017-001-00473-1)
through the Superintendent of Documents, Government Printing Office,
Washington, DC 20402-9325 (telephone 202-783-3238).

ELIGIBILITY REQUIREMENTS

Applications may be submitted by 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.
Minority individuals and women are encouraged to submit as Principal
Investigators.  Foreign institutions are not eligible for the First
Independent Research and Transition (FIRST) (R29) award.

MECHANISM OF SUPPORT

Support of this program will be through the NIH research project
grant (R01) and the FIRST (R29) award.  Responsibility for the
planning, direction, and execution of the proposed project will be
solely that of the applicant.  Awards will be administered under PHS
grants policy as stated in the PHS Grants Policy Statement.

This RFA is a one-time solicitation.  Generally, future unsolicited
competing continuation applications will compete with all
investigator-initiated applications and will be reviewed according to
the customary peer review procedures.  The total requested project
period for applications submitted in response to this RFA may not
exceed four years.  The earliest possible award date will be August
1, 1994.

FUNDS AVAILABLE

For FY 1994, $2,500,000 will be committed by the NIDDK to fund
applications submitted in response to this RFA.  The NHLBI has set
aside up to $800,000 for this purpose.  It is anticipated that 14 to
16 awards will be made.  However, this funding level is dependent
upon the receipt of a sufficient number of applications of high
scientific merit.  Applicants must limit their requests to not more
than $160,000 direct costs for the initial budget period.  Although
this program is provided for in the financial plans of the NIDDK and
the NHLBI, the award of grants pursuant to this RFA also is
contingent upon the availability of funds for this purpose.

It is anticipated that the majority of awards made from this RFA will
be for new projects.

RESEARCH OBJECTIVES

The purpose of this RFA is to solicit basic research applications
that propose to investigate the biology of hematopoietic stem cells
at the molecular and cellular level, with particular emphasis on
human cells. A major goal is to develop the means to use stem cells
as vehicles for gene therapy.  Studies are needed on isolation and
purification of stem cells, especially of human origin; improvement
of the ability to culture, maintain, and expand stem cells;
development of assays for human stem cells; description of the
behavior of human stem cells in in vivo systems; identification of
the factors controlling stem cell commitment, differentiation, and
cycling; stem cell trafficking, engraftment, and interactions; and
identification of stem cell-specific genes.

Stem cells represent a major potential resource for bone marrow
repopulation in bone marrow transplantation, as therapy for
malignancy, or in immunologic diseases and are principal targets for
gene therapy in the treatment of genetic diseases.  However, much
more needs to be learned about the biology of stem cells, before they
can be used routinely in these applications or in gene therapy.

Substantial progress has been made in the identification,
purification, and characterization of murine stem cells.  Long-term
repopulating cells can be separated from cells with short-term
repopulating potential and from CFU-S using physical methods and/or a
variety of immunological purification strategies.  The murine stem
cell has emerged as a small cell with lymphoid morphology in the deep
G0 phase of the cell cycle.  Major advances also have been made in
purifying early human hematopoietic cells using immunological methods
monitored by the capacity to form blast cell colonies or initiate
long-term persistence in reconstituted animal models.  The ability to
purify and assay human stem cells needs to be brought to these levels
of improvement.  Efforts must be directed to improve methods of
identification, selection and cultivation of human and other
mammalian stem cells.

The essential properties that define true stem cells are the capacity
for self-renewal and the ability to generate members of all
hematopoietic lineages during long-term repopulation of transplant
recipients.  Stem cells undergo both self-renewal division and cell
division, accompanied by differentiation reflected by commitment to a
progressively more restricted lineage repertoire.  An important key
to gene insertion using the currently available strategy involving
retroviral vectors appears to be the means to induce stem cells to
undergo self renewal division reproducibly and reliably in vitro
without loss of long term repopulating capacity.

Considerable improvement is needed in understanding how to infect the
pluripotent stem cells with viruses for persistent expression of
transfected genes and also in achieving high levels of expression.
Although several laboratories have achieved long-term expression in
mice, these problems remain obstacles to the use of human cells.  New
methods need to be developed to transfer genetic information to
hematopoietic stem cells, involving viral and physical methods of
gene transfer.  Related studies with hematopoietic progenitor cells
also may be of interest.

Accumulating evidence shows that stem cells respond to known
hematopoietic regulators including interleukins or colony stimulating
factors.  Studies are needed to determine how these regulators
influence the capacity for self-renewal versus differentiation
divisions.  The identification of growth regulators with effects on
primitive stem cells may have important implications for their
application to gene therapy, and could allow ex vivo expansion of
stem and progenitor cells for use in transplantation.

Topics that are included in the scope of this RFA include, but are
not limited to:

o  Identifying biochemical, immunological, morphological, and genetic
criteria for stem cells and progenitor cells.

o  Improving the methodology for hematopoietic stem cell
purification.

o  Developing protocols for routine isolation of highly purified stem
and progenitor populations.

o  Identifying new methods to assay stem and progenitor cells with
short- and long-term repopulation models amenable to serial
examination.

o  Identifying and defining the cytokines and growth factors that
have a positive or negative influence on the behavior of
hematopoietic stem cells.

o  Determining the role of cell-cell interactions between stromal and
stem cells in determining the capacity of the latter for self-renewal
and differentiation.

o  Identifying and cloning the homing receptors on hematopoietic stem
and progenitor cells.

o  Defining the factors or growth conditions that modulate
self-renewal, differentiation, or apoptosis of stem cells using
purified cells, recombinant growth factors and serum-free conditions.

o  Developing assays for quantitation of retroviral receptor
molecules on stem cells and determining conditions for influencing
their level of expression.

o  Developing new methods for stable insertion of genes into purified
stem cell populations.

Other objectives that applicants wish to propose to improve the
understanding of basic hematopoietic stem cell biology are welcomed.
Applications solely to apply existing knowledge to developing gene
therapy techniques using hematopoietic stem cells are not within the
scope of this RFA.

Program project grant applications (P01) will not be accepted in
response to this RFA.

STUDY POPULATIONS

SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH
POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL
RESEARCH STUDY POPULATIONS

NIH policy is that applicants for NIH clinical research grants and
cooperative agreements are required to include minorities in study
populations so that research findings can be of benefit to all
persons at risk of the disease, disorder or condition under study;
special emphasis must be placed on the need for inclusion of
minorities in studies of diseases, disorders and conditions which
disproportionately affect them.  This policy is intended to apply to
males of all ages.  If minorities are excluded or inadequately
represented in clinical research, particularly in proposed
population-based studies, a clear compelling rationale must be
provided.

The composition of the proposed study population must be described in
terms of racial/ethnic groups.  In addition, racial/ethnic issues
must be addressed in developing a research design and sample size
appropriate for the scientific objectives of the study.  This
information must be included in the form PHS 398 (rev. 9/91) in Item
4 (Research Design and Methods) of the Research Plan AND summarized
in Item 5, Human Subjects. Applicants are urged to assess carefully
the feasibility of including the broadest possible representation of
minority groups. However, NIH recognizes that it may not be feasible
or appropriate in all research projects to include representation of
the full array of United States racial/ethnic minority populations;
i.e., Native Americans [including American Indians or Alaskan
Natives], Asian/Pacific Islanders, Blacks, Hispanics.

The rationale for studies on single minority population groups should
be provided.

For the purpose of this policy, clinical research is defined as human
biomedical and behavioral studies of etiology, epidemiology,
prevention (and preventive strategies), diagnosis, or treatment of
diseases, disorders or conditions, including but not limited to
clinical trials.

The usual NIH policies concerning research on human subjects also
apply.  Basic research or clinical studies in which human tissues
cannot be identified or linked to individuals are excluded.  However,
every effort should be made to include human tissues from
racial/ethnic minorities when it is important to apply the results of
the study broadly, and this should be addressed by applicants.

If the required information is not contained within the application,
the application will be returned without review.

Peer reviewers will address specifically whether the research plan in
the application conforms to these policies.  If the representation of
minorities in a study design is inadequate to answer the scientific
question(s) addressed AND the justification for the selected study
population is inadequate, it will be considered a scientific weakness
or deficiency in the study design and reflected in assigning the
priority score to the application.

All applications for clinical research submitted to NIH are required
to address these policies.  NIH funding components will not award
grants or cooperative agreements that do not comply with these
policies.

LETTER OF INTENT

Prospective applicants are requested, but not required, to submit a
letter of intent to apply to the RFA.  This letter should include the
name, telephone number, and mailing address of the Principal
Investigator, the names of other key personnel, the name of the
applicant institution, and the number and title of this RFA.  Such 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 application.  Letters of intent are requested solely
for planning purposes.  NIDDK staff will not provide responses to
such letters.  Letters of intent must be received no later than
November 18, 1993 and are to be addressed to:

Dr. Robert Hammond
Chief, Review Branch
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 9/91) is to be used
in applying for these grants.  The form is available from most
institutional offices of sponsored research and from the Office of
Grants Information, Division of Research Grants, National Institutes
of Health, 5333 Westbard Avenue, Room 449, Bethesda, MD 20892,
telephone (301) 710-0267.

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 a Principal Investigator must be included
with the application.

The RFA label available in the application form must be affixed to
the bottom of the face page.  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 check the YES box.

Submit a signed, typewritten original of the application, including
the Checklist, and three signed, exact photocopies, in one package
to:

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

At time of submission, two additional copies of the application must
also be sent under separate cover to:

Chief, Review Branch
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 605
Bethesda, MD  20892

Applications must be received by January 18, 1994.  If an application
is received after that date, it will be returned to the applicant.
The Division of Research Grants (DRG) will not accept any application
in response to this announcement that is essentially the same as one
currently pending initial review, unless the applicant withdraws the
pending application.  However, it is allowable to submit the same
project as both an R01 and as a component project of a program
project.  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 previously
reviewed.  Such applications must not only include an introduction
addressing the previous critique but also be responsive to this RFA.

FIRST Award (R29) applications must include at least three sealed
letters of reference attached to the face page of the original
application.  FIRST Award applications submitted without the required
number of reference letters will be considered incomplete and will be
returned without review.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by the DRG for
completeness.  Incomplete applications will be returned to the
applicant without further consideration.  Evaluation for
responsiveness to the program requirements and criteria stated in the
RFA is an NIDDK staff function.  If the application is not responsive
to the RFA, the staff will contact the applicant to determine whether
it should be returned to the applicant or held until the next regular
receipt date and reviewed in competition with all other applications.

Those applications that are complete and responsive will be evaluated
in accordance with the criteria stated below for scientific/technical
merit by an appropriate peer review group convened by the NIDDK.
Applications may be subjected to triage by an NIDDK-convened peer
review group to determine their scientific merit relative to other
applications received in response to this RFA.  If the number of
applications is large compared to the number of awards to be made, a
preliminary scientific peer review may be conducted and applications
withdrawn from further competition when they are not competitive for
the award.  The NIDDK staff will notify the applicant and
institutional official of this action.

Those applications judged to be competitive will be reviewed for
scientific and technical merit in accordance with the usual NIH peer
review procedures by an initial review group specifically convened
for this RFA.  Following this review, the applications will be given
a secondary review by the National Diabetes and Digestive and Kidney
Diseases Advisory Council and by the National Heart, Lung, and Blood
Advisory Council, unless not recommended for further consideration by
the initial review group.

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

o  scientific/technical merit criteria specific to the objectives of
the RFA;

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 resources necessary to perform the research;

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

o  if an application involves activities that could have an adverse
effect upon humans, animals, or the environment, the adequacy of the
proposed means for protecting against or minimizing such effects.

o in addition, reviewers will be asked to address the new and
innovative character of the proposal; applicants should ensure that
those factors are delineated in the application.

AWARD CRITERIA

Funding decisions will be made based on the initial review group and
national advisory council recommendations, program relevance, and
availability of funds.

INQUIRIES

Written and telephone inquiries concerning this RFA are encouraged.
Direct inquiries regarding programmatic issues to:

David G. Badman, Ph.D.
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A-05
Bethesda, MD  20892
Telephone:  (301) 594-7541
FAX:  (301) 594-7501

Alan S. Levine, Ph.D.
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
Federal Building, Room 5A12
Bethesda, MD  20892
Telephone:  (301) 496-5911
FAX:  (301) 496-9940

Inquiries regarding fiscal matters may be directed to:

Ms. Trude McCain
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 649
Bethesda, MD  20892
Telephone:  (301) 594-7543

Schedule

Letter of Intent Receipt Date:  November 18, 1993
Application Receipt Date:       January 18, 1994
Initial Review:                 March 1994
Second Level Review:            May 1994
Anticipated Date of Award:      August 1, 1994

AUTHORITY AND REGULATIONS

This program is described in the Catalog of Federal Domestic
Assistance No. 93.849 (NIDDK) .  Awards are made under 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 requirements of Executive Order 12372 or
Health Systems Agency review.

.

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