Full Text PA-96-043
 
LINEAGE-SPECIFIC DIFFERENTIATION OF HEMATOPOIETIC STEM CELLS
 
NIH GUIDE, Volume 25, Number 13, April 26, 1996
 
PA NUMBER:  PA-96-043
 
P.T. 34

Keywords: 
  Cancer/Carcinogenesis 
  Biology, Cellular 
  Biology, Molecular 
  0705048 

 
National Institute of Diabetes and Digestive and Kidney Diseases
National Cancer Institute
 
PURPOSE
 
The National Institute of Diabetes and Digestive and Kidney Diseases
(NIDDK), through its Division of Kidney, Urologic and Hematologic
Diseases, and the National Cancer Institute (NCI), through its Cancer
Immunology Branch, support fundamental and applied research aimed at
understanding the fundamental processes underlying the normal and
pathologic function of blood cells and the blood forming system.
 
The processes of lineage-specific differentiation of the
hematopoietic stem cells are central to the maintenance of normal
hematopoiesis.  An increased understanding of the molecular
mechanisms controlling these events would increase our ability to
combat selective cytopenias, and could facilitate hematopoietic
reconstitution following radiation, chemotherapy, and marrow
transplantation.  Also, leukemias and lymphomas usually are regarded
as hematopoietic cells frozen at various stages of differentiation.
Elucidation of the basic mechanism of the differentiation process is
important to our understanding of leukemogenesis and lymphomagenesis.
 
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.  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.
Foreign institutions are not eligible for First Independent Research
Support and Transition (FIRST) (R29) awards. Racial/ethnic minority
individuals, women, and persons with disabilities are encouraged to
apply as principal investigators.
 
MECHANISM OF SUPPORT
 
This PA will use the National Institutes of Health (NIH) individual
research project grant (R01) and FIRST (R29) award mechanisms.
Responsibility for the planning, direction, and execution of the
proposed project will be solely that of the applicant.  Because the
nature and scope of the research proposal in response to this PA may
vary, it is anticipated that the size of an award will vary also;
however, the support of requests exceeding the NIDDK average grant
size of $160,000 direct cost for R01 grants would be unusual and
require ample justification. FIRST (R29) awards are limited to
$350,000 direct cost over the five year period.
 
RESEARCH OBJECTIVES
 
The purpose of this PA is to promote the identification and
characterization of the gene expression involved in hematopoietic
cell regulation including, but not restricted to:  (1) Stem cell
self-renewal or commitment; (2) Expression of growth factor receptors
as part of the commitment process of stem cells; (3)
Developmentally-related changes in stem cell biology and
differentiation.
 
These studies should provide insight into the fundamental processes
involved in the maintenance of the stem cell compartment and its
production of committed progenitor cells through the lifespan of the
organism.
 
Applications are solicited that are centered around investigations
into the mechanisms of gene regulation during hematopoietic cell
maturation and differentiation. Of particular interest is the
elucidation of specific DNA sequences, DNA binding proteins, signal
transduction mechanisms, extracellular matrix proteins, and
cell-surface proteins that influence gene expression.  For instance,
recently it has become evident that beta-2 integrins are not simply
adhesion sites on the cell surface of hematopoietic cells but may
modulate a number of cellular processes including signal transduction
pathways and gene expression.  Thus, integrins may be part of the
signal transduction pathways that include growth factors, growth
factor receptors, tyrosine kinases and phosphatases.
 
Many opportunities for basic research exist in the control of the
genes expressed in various hematopoietic lineages.  A major
development of the last ten years in understanding the
differentiation of the erythroid lineage has been the discovery of
the Locus Control Region that lies upstream of the  beta-globin gene
locus.  This novel regulatory element activates the chromatin domain,
confers erythroid lineage specific expression of linked genes, and is
a powerful enhancer.  The mechanism of action of this element remains
unknown.  Delineation will be important for achieving gene therapy of
the  beta-chain hemoglobinopathies.
 
Other recently described regulatory elements also require
investigation.  Silencers have been identified for embryonic and
fetal globin genes but the mechanism of their action is unknown.
Recently, sequences which can insulate genes from the effects of
surrounding chromatin have been identified.  Delineation of these
sequences and understanding their mechanisms of action will have a
major impact on gene transfer technology.  Trans-acting factors that
control the developmental pattern of globin gene expression have been
postulated on the basis of experimental data but their identities
remain unknown.  Other areas include the identification of new
lineage-specific transcriptional factors or cell surface receptors,
and their mechanisms of action.  Little is known about the control of
many of the known hematopoietic genes at the transcriptional level,
including those for structural proteins, enzymes and receptors.
 
A more complete understanding of the normal control of hematopoietic
cell differentiation and the abnormal processes leading to
pathogenesis will increase our understanding of hematologic diseases
and will aid the development of rational therapies.
 
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
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, Volume 23, Number 11,
March 18, 1994.
 
Investigators also may obtain copies of the policy from the program
staff listed under INQUIRIES.  Program staff may also provide
additional relevant information concerning the policy.
 
ANIMAL WELFARE CONSIDERATIONS
 
Investigators are encouraged to consider alternative methods and
approaches in their research grant applications that do not require
the use of whole animals, use alternative species such as nonmammals
or invertebrates, reduce the number of animals required, and
incorporate refinements to procedures that will result in the
elimination or further minimization of pain and distress in animals.
 
APPLICATION PROCEDURES
 
Applications are to be submitted on the grant application form PHS
398 (rev. 5/95) and will be accepted at the standard application
deadlines as indicated in the application kit.  Application kits are
available at most institutional offices of sponsored research, or may
be obtained from the Grants Information Office, Office of Extramural
Outreach and Information Resources, National Institutes of Health,
6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone
301/710-0267, Email: asknih@odrockm1.od.nih.gov.
 
The program announcement title and number must be typed on line 2 of
the face page of the application form and the YES box must be marked.
 
Applications for the FIRST Award (R29) must include at least three
sealed letters of reference attached to the face page of the original
application.  FIRST Award (R29) applications submitted without the
required number of reference letters will be considered incomplete
and will be returned without review.
 
Potential R29 applicants should refer to the announcement on
Just-in-Time Procedures for FIRST and Career Awards (NIH Guide for
Grants and Contracts, Vol. 25, No. 10, March 29, 1996) for
information on recent changes in guidelines for FIRST award format.
 
The completed original application and five legible copies must be
sent or delivered to:
 
DIVISION OF RESEARCH GRANTS
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD 20892-7710
BETHESDA, MD 20817 (for express/courier service)
 
REVIEW CONSIDERATIONS
 
Although this is a Program Announcement sponsored by the National
Institute of Diabetes and Digestive and Kidney Disease and by the
National Cancer Institute, the National Heart, Lung, and Blood
Institute also has an interest in the subject matter of this PA.
Other Institutes/Centers of the NIH also may have an interest.
Applications will be assigned to the most appropriate
Institute/Center on the basis of established Public Health Service
referral guidelines.
 
Applications will be reviewed for completeness by the Division of
Research Grants (DRG).  Applications that are complete will be
evaluated for scientific and technical merit by an appropriate peer
review group convened in accordance with 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.
 
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 proposed 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.
 
For Applications from Foreign Organizations:
 
o  availability of special opportunities for furthering research
programs through the use of unusual talent resources, populations, or
environmental conditions in other countries that are not readily
available in the United States or that provide augmentation of
existing U.S. resources.
 
AWARD CRITERIA
 
Applications will compete for available funds with other approved
applications assigned to that IC.  The following will be considered
in making funding decisions:
 
o  Quality of the proposed project as determined by peer review;
o  Availability of funds;
o  Program priority.
 
INQUIRIES
 
Inquiries are encouraged.  The opportunity to clarify any issues or
questions from potential applicants is welcome. Direct inquiries
regarding programmatic issues to either of the following:
 
David G. Badman, Ph.D.
Division of Kidney, Urologic and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney
Diseases 45 Center Drive, Room AS-13C MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  David_Badman@nih.gov
 
Grace L. Shen, Ph.D.
Division of Cancer Biology
National Cancer Institute
6130 Executive Boulevard, Room 501
Rockville, MD  20892-7381
Telephone:  (301) 496-7815
FAX:  (301) 496-8656
Email:  Grace_Shen@nih.gov
 
Inquiries regarding fiscal matters may be directed to either of the
following:
 
Aretina Perry
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases
45 Center Drive, Room 6AN-38B, MSC 6600
BETHESDA, MD  20892-6600
Telephone:  (301) 594-8862
Email:  PerryA@ep.niddk.nih.gov
 
Sara Stone
Grants Management Branch
National Cancer Institute
6120, Executive Boulevard, Room 243
Rockville, MD  20892
Telephone:  (301)496-7800 X266
Email:  Stones@gab.nci.nih.gov
 
AUTHORITY AND REGULATIONS
 
This program is described in the Catalog of Federal Domestic
Assistance No. 93.849.  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.
 
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 PHS
mission to protect and advance the physical and mental health of the
American people.
 
.

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