Full Text HL-95-008

HUMAN STEM CELL SOURCES AND TRANSPLANTATION BIOLOGY

NIH GUIDE, Volume 23, Number 39, November 4, 1994

RFA:  HL-95-008

P.T. 34

Keywords: 
  Transplantation Immunology 
  Cell Lines 
  Biology, Cellular 


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

Letter of Intent Receipt Date:  February 13, 1995
Application Receipt Date:  March 16, 1995

PURPOSE

The Cellular Hematology Scientific Research Group, Blood Diseases
Program, Division of Blood Diseases and Resources, NHLBI and the
National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK) announce the availability of a Request for Applications (RFA)
on the above subject.  The purpose of this initiative is to encourage
research aimed at providing a better understanding of the differences
between stem/progenitor cells from different sources such as bone
marrow, peripheral circulation of children and adults and
placental/cord blood.  Important studies to be pursued entail the
characterization of stem/progenitor cells for self-renewal,
proliferation, and expansion and the mechanisms involved in these
processes.  Also to be studied are the immune cells present in the
different tissue sources, and the mechanisms of their action in graft
vs. host disease, and in graft vs. leukemia effect.  The ultimate
goal is to identify the most appropriate cell populations capable of
sustaining long-term hematopoiesis in humans treated for malignant
and non-malignant diseases.

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, Human Stem Cell Sources and Transplantation Biology, is
related to the priority area 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 "Healthy People
2000" (Summary Report:  Stock No. 017-001-00473-1) through the
Superintendent of Documents, Government Printing Office, Washington,
DC 20402-9325 (telephone 202-782-3238).

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 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.  Foreign institutions are not
eligible for First Independent Research Support and Transition
(FIRST) (R29) awards.  Applications from minority individuals and
women are encouraged.

MECHANISM OF SUPPORT

This RFA will use the National Institutes of Health (NIH) individual
research project grant (R01) and FIRST (R29) award and is a one-time
solicitation.  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.  For R01 grants, up to four years of support may be
requested.  FIRST (R29) awards must be for five years.  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 or the NIDDK.  It is anticipated that support
for the present program will begin in September 1995.  Administrative
adjustments in project period and/or amount of support may be
required at the time of the award.  All current policies and
requirements that govern the research grant programs of the NIH will
apply to grants awarded in response to this RFA.

FUNDS AVAILABLE

Fiscal Year 1995 financial plans for the NHLBI include $1.5 million
for this program.  The NIDDK plans to allocate an additional
$500,000.  However, award of grants pursuant to this RFA is
contingent upon receipt of funds for this purpose.  It is anticipated
that the NHLBI will award approximately five new grants under this
program and the NIDDK about two.  The specific amount to be funded
will, however, depend on the merit and scope of the applications
received and on the availability of funds.  Since a variety of
approaches would represent valid responses to this RFA, it is
anticipated that there will be a range of costs among individual
grants awarded.  If collaborative arrangements involve sub-contracts
with other institutions, the NHLBI Grants Management Staff (tel:
301-594-7436) should be consulted regarding procedures to be
followed.  Designated funding levels and/or project period duration
are subject to change at any time prior to award, due to unforeseen
budgetary, administrative and/or scientific developments.

RESEARCH OBJECTIVES

The major objective of this initiative is to encourage research aimed
at providing a better understanding of the differences between
stem/progenitor cells from different sources such as bone marrow,
peripheral circulation of children and adults and placental/cord
blood.  Recent studies suggest that there may be important
differences between the various sources of transplantable
hematopoietic stem/progenitor cells.  Important studies to be pursued
entail the characterization of stem/progenitor cells for self-
renewal, proliferation, and expansion and the mechanisms involved in
these processes.  Also to be studied are the immune cells present in
the different tissue sources, and the mechanisms of their action in
graft vs. host disease, and in graft vs. leukemia effect.  The
ultimate goal is to identify the most appropriate cell populations
capable of sustaining long-term hematopoiesis in humans treated for
malignant and non-malignant diseases.

Circulating Stem/Progenitor and Immune Cells

Studies of over 45 cord blood transplants performed so far for a
number of malignant (AML, ALL, CML, JCML, solid tumor) and non-
malignant (Fanconi anemia, aplastic anemia, inborn errors of
metabolism, Wiscott-Aldrich, x-linked lymphoproliferative disease,
and beta thalassemia) diseases in children suggest that graft vs.
host disease (GVHD) has been very low with this source of engrafting
cells.  Additionally, growth factor- and/or chemotherapy mobilized
adult peripheral blood stem/progenitor cells are fast becoming a
source of transplantable autologous, and to a lesser extent,
allogeneic stem/progenitor cells.  Therefore, a comparative
assessment of the utility of cord blood, bone marrow and mobilized
peripheral blood, in both autologous and related/unrelated allogeneic
transplantation, are important studies to be pursued.  The assessment
would include characterization of potential differences in the
quality of stem and progenitor cells from these different sources in
terms of their capacity for proliferation, self-renewal, expansion,
and their responsiveness to cytokines and stromal cells.  Studies of
the mechanisms of GVH and graft vs. leukemia (GVL) effects of subsets
of blood lymphocytes, natural killer cells, and lymphokine-activated
killer cells from the various tissue sources are needed.

Future efforts in the area of chemotherapy- and/or growth factor-
induced mobilized adult peripheral blood stem/progenitor cells should
include: (a) optimization of mobilization techniques, better
characterization of the cells mobilized and whether the use of
different growth factors, at various doses and times will
differentially recruit different subsets of stem and progenitor
cells; (b) determination of whether or not the earliest long-term
marrow engrafting cells are present in mobilized adult peripheral
blood; and (c) determination of whether long-term engraftment is due
to the infused cells, or if the infused population only contains
shorter-term repopulating cells, which allow the donor/recipient
time for repopulation by endogenous, non-transplanted cells.  This
latter possibility has not been adequately studied, and may result
from the less myeloablative regimens used for autologous, as compared
to allogeneic transplantation.  Efforts here would require marking,
perhaps using retroviral vectors, of the mobilized, removed and
autologously transplanted cells.

Of considerable importance would be to study the capacity of these
different sources of stem and progenitor cells, such as cord blood
versus bone marrow, to serve as cellular vehicles for gene therapy.
Efforts aimed at the comparative efficacy of gene transduction of
subsets of these cells, especially those of the most immature
populations, including long-term marrow repopulating cells, could
hasten the use of gene therapy for the treatment of malignant and
non-malignant diseases.  Comparative cellular, molecular biological
and transplantation immunological studies of these cell sources could
provide critical information required to engineer the graft product
to provide the maximum therapeutic benefit in a variety of clinical
diseases states.

The above examples of research approaches are not meant to be all
inclusive or restrictive.  Investigators are encouraged to develop
their own innovative approaches to achieve the goals of this
initiative.  However, the proposed studies should focus on cells of
human origin but xenogeneic animal models for growth of human cells
can be considered as possible models for study of the earliest human
stem cells.

Exclusions

Epidemiological studies, large-scale clinical trials, and large
multi-project grant applications (program project grants) are
specifically excluded from this RFA.

SPECIAL REQUIREMENTS

Upon initiation of the program, the NHLBI and the NIDDK will sponsor
annual meetings to encourage an exchange of information among
investigators who participate in this program.  In preparing the
budget for the grant application, applicants should request
additional travel funds for 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 the research.  This new policy results
from the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some 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 below.  Program staff may also
provide additional relevant information concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by February 13, 1995, 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.  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, will not enter into the review of any application
subsequently submitted, nor is it a necessary requirement for the
application.  The letter of intent is to be sent to:

Dr. James Scheirer
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 557A
Bethesda, MD  20892
Telephone:  (301) 594-7478
FAX:  (301) 594-7407
email:  James_Scheirer@NIH.Gov

APPLICATION PROCEDURES

Application Receipt Date:  March 16, 1995

Applications are to be submitted on the research grant application
form PHS 398 (rev. 9/91).  This form is available at 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) 435-0714.  Use the conventional format for research-
project grant applications and ensure that the points identified in
the section REVIEW CONSIDERATIONS are fulfilled.  FIRST applications
must include at least three sealed letters of reference attached to
the face page of the original application.  FIRST applications
submitted without the required number of reference letters will be
considered incomplete and will be returned without review.

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.  To identify the application as a
response to this RFA, check "YES" on Item 2a of page 1 of the
application and enter the title and RFA Number:  HUMAN STEM CELL
SOURCES AND TRANSPLANTATION BIOLOGY RFA HL-95-008.

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:

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

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 (DRG).  Otherwise
the NHLBI cannot guarantee that the application will be reviewed in
competition for this RFA.

Applications must be received by March 16, 1995.  An application not
received by this date will be returned to the applicant without
review.  The 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 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.

Although this RFA is a co-sponsored by the NHLBI and the NIDDK, the
National Institute of Allergy and Infectious Diseases (NIAID) and the
National Cancer Institute (NCI) also have an interest in research
focused at better understanding the differences between
stem/progenitor cells from different sources, including peripheral
blood.  The NCI also has an interest in research focused on immune
functions and graft-versus leukemia mechanisms.  Therefore, the NIAID
or the NCI may be given an institute assignment, as appropriate, in
accordance with NIH referral guidelines.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed for completeness and
responsiveness by the NIH.  Grant applications will be assigned
according to standard referral guidelines.  Incomplete applications
and applications deemed not responsive to the RFA 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 (triage) 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
promptly notified.

The criteria used in evaluating the scientific merit of each
application will be similar to those used in the review of
traditional research project grant applications, including the
novelty, originality, and feasibility of the approach; the training,
experience and research competence of the investigator(s); the
adequacy of the experimental design; the suitability of the
facilities; the appropriateness of the requested budget to the work
proposed; and the adequacy of plans to include both genders and
minorities and their subgroups as appropriate for the scientific
goals of the research.

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

AWARD CRITERIA

The anticipated award date is September 1995.  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.

In order to more evenly distribute administrative workload and reduce
the number of awards with July 1 or September 30 start dates, ten
months of time and money will be awarded for the first competing
budget period of this project.  This action results in a project
period of 46 months rather than 48 months for R01 applications.
Investigators should plan their research projects and budgets within
these time frames.

INQUIRIES

Inquiries concerning this RFA are encouraged.  The opportunity to
clarify any issues or questions from potential applicants is welcome.

Helena O. Mishoe, 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
Email:  Helena_Mishoe@NIH.Gov

David G. Badman, Ph.D.
Division of Kidney, Urologic, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Westwood Building, Room 3A05
Bethesda, MD  20892
Telephone:  (301) 594-7541
FAX:  (301) 594-7501
Email:  davidb@dvsgate.niddk.nih.gov

Direct inquiries regarding fiscal matters to:

Ms. Jane R. Davis
Division of Extramural Affairs
National Heart, Lung, and Blood Institute
Westwood Building, Room 4A11
Bethesda, MD  20892
Telephone:  (301) 594-7436
FAX:  (301) 594-7492
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 No.
93.839.  Awards are 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
Health Systems Agency review.

The Public Health Service (PHS) strongly encourages all grant
recipients to provide a smoke-free workplace and promote the non-use
of all tobacco products.  This is consistent with the PHS mission to
protect and advance the physical and mental health of the American
people.

.

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