Full Text HL-96-020
 
HOMING DETERMINANTS IN HEMATOPOIETIC STEM/PROGENITOR CELLS
 
NIH GUIDE, Volume 25, Number 24, July 19, 1996
 
RFA:  HL-96-020
 
National Heart, Lung, and Blood Institute
National Institute of Diabetes and Digestive and Kidney Diseases
 
P.T. 34

Keywords: 
  Biology, Cellular 
  Immunology 

 
Letter of Intent Receipt Date:  September 25, 1996
Application Receipt Date:  October 25, 1996
 
THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS.  THIS RFA
INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS
THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS
RFA.
 
PURPOSE
 
The Cellular Hematology Scientific Research Group, Division of Blood
Diseases and Resources, NHLBI, and the Hematology Program, Division
of Kidney, Urology, and Hematologic Diseases, NIDDK, announces the
availability of a Request of Applications (RFA) on the above subject.
The purpose of this initiative is to encourage research aimed at
delineating the function and regulation of homing determinants and
their receptors (or ligands) that are involved in regulation of
growth and differentiation of hematopoietic stem and progenitor
cells.  It is conceivable that the exquistive specificity  of the
hematopoietic homing process is determined by combinatorial "decision
processes" involving multistep sequential engagement of overlapping
regulatory, adhesion, and migratory events.  However, this important
process is poorly understood. The initiative will identify the
cascade of interactive events in early phases of hematopoietic cell
differentiation and its relation to engraftment.  A major aspect of
the program is to encourage research on the stem cell homing receptor
or receptors and methods to manipulate receptor expression and
binding. Such studies will undoubtedly have a major impact on our
ability to identify the factors that are involved in such critical
functions such as stem cell self-renewal, maintenance of progenitor
cells, bone marrow and stem cell engraftment, and graft maintenance
and rejection.
 
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, Homing Determinants in Hematopoietic Stem and Progenitor
Cells, 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. 017-001-00473-1) 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 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.  Minority individuals and
women are encouraged to apply.
 
MECHANISM OF SUPPORT
 
This RFA will use the NIH individual research project grant (R01)
mechanism of support.  Newly independent investigators who may wish
to consult with a program representative (see INQUIRIES section) are
encouraged to apply.  Specific application instructions have been
modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining
efforts being examined by the NIH.  The modular grant concept
establishes specific modules in which direct costs may be requested
as well as a maximum level for requested budgets.  Only limited
budgetary information is required under this approach.  The just-in-
time concept allows applicants to submit certain information only
when there is a possibility for an award.  It is anticipated that
these changes will reduce the administrative burden for the
applicants, reviewers and Institute staff.
 
For this RFA, funds must be requested in $25,000 direct cost modules
and a maximum of seven modules ($175,000 direct costs) per year may
be requested.  Any necessary escalation must be included within the
number of modules being  requested.  Only limited budget information
will be required and any budget adjustments made by the Initial
Review Group will be in modules of $25,000.  Instructions for
completing the Biographical Sketch have also been modified.  In
addition, Other Support information and the application Checklist
page are not required as part of the initial application.  If there
is a possibility for an award, necessary budget, Other Support and
Checklist information will be requested by NHLBI staff following the
initial review.  The APPLICATION PROCEDURES section of this RFA
provides specific details of modifications to standard PHS 398
application kit instructions.
 
Applicants, 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.  Up to 4
years of support may be requested.  At the end of the official award
period, renewal applications may be submitted for peer review and
competition for support through the regular grant program of the
NHLBI and NIDDK.  It is anticipated that support for the present
program will begin August 1997.  Administrative adjustments in
project period or amount of support may be required at the time of
the award.  Since a variety of approaches would represent valid
responses to this announcement, it is anticipated that there will be
a range of costs among individual grants awarded.  All current
policies and requirements that govern the research grant programs of
the NIH will apply to grants awarded in connection with this RFA.
 
FUNDS AVAILABLE
 
It is anticipated that for fiscal year 1997, $1,500,000 total costs
will be available for the first year of support for this initiative
by the NHLBI.  Award of grants pursuant to this RFA is contingent
upon receipt of such funds for this purpose.  It is anticipated that
approximately five to six new grants will be awarded under this
program.  The NIDDK plans to allocate an additional $500,000 in total
costs for the first year of support and plans to fund up to two
applications.  Applicants may request up to four years of support.
The specific number to be funded will, however, depend on the merit
and scope of the applications received and on the availability of
funds.  Direct costs will be awarded in modules of $25,000, less any
overlap or other necessary administrative adjustments.  Indirect
costs will be awarded based on the negotiated rates.  If
collaborative arrangements involve subcontracts with other
institutions, Ms. Jane R. Davis of the NHLBI Grants Operations Branch
(telephone: (301) 435-0166) should be consulted regarding procedures
to be followed.
 
RESEARCH OBJECTIVES
 
Background
 
The production of blood cells, a process called hematopoiesis, takes
place in the bone marrow.  Hematopoiesis begins with the most
primitive, pluripotent hematopoietic stem cell which is believed to
be present as only one of every 100,000 nucleated bone marrow cells.
The stem cell can either self-renew or differentiate into myeloid or
lymphoid stem cells, which in turn can further differentiate 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 (colony stimulating
factors) or cytokines that enhance cellular proliferation and
maturation, or they exert negative or inhibitory effects on the
process.
 
Hemopoietic growth factors can be divided into two major groups (1):
Those factors that are usually soluble and may reach hemopoietic
cells via blood the stream.  They tend to act on more differentiated
cells, affecting their growth and maturation.  They display little or
no synergism with other growth factors.  Examples of factors in this
group are erythropoietin and G-CSF.  There exists a second group of
hemopoietic factors that can act on earlier, usually undifferentiated
progenitor cells.  The factors and their ligand are generally
membrane-bound (2,3) and they constitute the molecular basis of cell-
cell interaction (progenitor cell-stromal cells) (2).  In addition
these factors may not necessarily be "growth" factors since their
actions are not typically stimulatory.  They may also be involved in
such critical functions stem cell self-renewal, stem cell
engraftment, and graft maintenance or rejection.  Although these
functions may not belong strictly to the category of growth factors,
stimulatory or inhibitory, their function may ultimately lead to one
of the others.  The factors moreover, are usually inactive by
themselves and require the synergistic effect of other similar
factors.  Their interactions appear to form a cascade that leads to
differentiation of cells that can later be subject to the effect of
soluble, late-acting growth factors.  Hence, it is owing to these
membrane-associated factors that during early stages of development,
the cell membrane is the arena of regulating interactions.  Examples
of these membrane-associated factors are the homing receptor-ligand
(4) and the c-kit receptor and ligand (5).  To this group should be
added certain extracellular matrix components such as proteoglycans
and fibronectin that could themselves be membrane-associated or
interact with other membrane-associated factors (6).
 
Whereas the soluble group of the growth factors and their respective
ligands have been the subject of intensive and extensive studies and
much of their clinical applications has been (or are being) defined,
we are just beginning to learn the importance of the
membrane-associated group and the cascade of their interactions.
 
A major difficulty has been the availability of relatively purified
stem cells or early progenitor cells, whose membrane is the area of
action and interaction of these factors.  These early progenitor
cells are needed in relatively purified form and in quantities that
can permit the application of modern cellular and molecular
biological techniques.  Such techniques are now gradually becoming
available (7,8) and may help to reconstruct a cascade of interactive
events in early phases of hemopoietic cell differentiation.
 
The goals of this program are to identify this cascade of interactive
events, its relation to engraftment, and its function in the
maintenance of progenitor cells.  A related goal is the development
of methods such as amplification of purified progenitor cells.  The
ultimate goal is to identify the potentials of this cascade for
exploitation in various clinical states and in particular in bone
marrow transplantation.  For example, a major aspect of this
initiative is to encourage research on the stem cell homing
receptor(s) and methods to manipulate receptor expression or receptor
binding.  Such studies may eventually be useful as a means for
improving marrow and stem cell transplantation.These suggested
approaches are intended as examples only.  Investigators are
encouraged to consider other innovative approaches.
 
SPECIAL REQUIREMENTS
 
Upon initiation of the program, the NHLBI and the NIDDK will sponsor
annual meetings to encourage the exchange of information among
investigators who participate in this program.  In the preparation of
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 applications indicating their willingness to participate in such
meetings.
 
INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN
SUBJECTS
 
It is the policy of the NIH that women and members of minority groups
and their subpopulations must be included in all NIH supported
biomedical and behavioral research projects involving human subjects,
unless a clear and compelling rationale and justification is provided
that inclusion is inappropriate with respect to the health of the
subjects or the purpose of research.  This new policy results from
the NIH Revitalization Act of 1993 (Section 492B of Public Law
103-43) and supersedes and strengthens the previous policies
(Concerning the Inclusion of Women in Study Populations, and
Concerning the Inclusion of Minorities in Study Populations) which
have been in effect since 1990.  The new policy contains some new
provisions that are substantially different from the 1990 policies.
All investigators proposing research involving human subjects should
read the "NIH Guidelines for Inclusion of Women and Minorities as
Subjects in Clinical Research", which have been published in the
Federal Register of March 28, 1994 (FR 59 14508-14513), and reprinted
in the NIH GUIDE FOR GRANTS AND CONTRACTS of March 18, 1994, Volume
23, Number 11.
 
Investigators may obtain copies from these sources or from the
program staff or contact person listed below.  Program staff may also
provide additional relevant information concerning the policy.
 
LETTER OF INTENT
 
Prospective applicants are asked to submit, by September 25, 1996, a
letter 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, and it
will not enter into the review of any application subsequently
submitted, nor is it a necessary requirement for the application.  A
faxed letter of intent may be used in place of a posted one.
 
This letter of intent is to be sent to:
 
Chief, Review Branch
Division of Extramural Affairs, NHLBI
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7924
Bethesda, MD  20892-7924
Telephone:  (301) 435-0266
FAX:  (301) 480-3541
Email:  james_scheirer@nih.gov
 
APPLICATION PROCEDURES
 
Application Receipt Date: October 25, 1996
 
Applications are to be submitted on the research grant application
form PHS 398 (rev. 5/95).  Applications kits are available at most
institutional offices of sponsored research and 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 301/435-0714,
email:  ASKNIH@odrockm1.od.nih.gov.  Use the conventional format for
research grant applications and ensure that the points identified in
the section on REVIEW CONSIDERATIONS are fulfilled.
 
Budget Instructions
 
The total direct costs must be requested in accordance with the
program guidelines and the modifications made to the standard PHS 398
application instructions described below:
 
DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form
Page 4 of the PHS 398 (rev 5/95).  It is not required nor will it be
accepted at the time of application.
 
BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT -  Do not complete
the categorical budget tables on Form page 5 of the PHS 398 (rev.
5/95). Only the requested total direct costs line for each year must
be completed based on the number of $25,000 modules being requested.
Applicants may not request a change in the amount of each module.  A
maximum of seven modules ($175,000)direct costs per year may be
requested and each applicant may request up to four years of support
for this RFA.  Direct cost budgets will remain constant throughout
the life of the project (i.e. the same number of modules requested
for all budget periods).  Any necessary escalation should be
considered when determining the number of modules to be requested.
However, in the event that the number of modules requested must
change in any future year due to the nature of the research proposed,
appropriate justification must be provided.  Total Direct Costs for
the entire Proposed Project Period should be shown in the box
provided.
 
BUDGET JUSTIFICATION -
- Budget justifications should be provided under "Justifications" on
Form Page 5 of the PHS 398.
- List the names, role on the project and proposed percent effort for
all project personnel (salaried or unsalaried)and provide a narrative
justification for each person based on his/her role on the project. -
Identify all consultants by name and organizational affiliation and
describe the services to be performed.
- Provide a general narrative justification for individual categories
(equipment, supplies, etc.) required to complete the work proposed.
More detailed justifications should be provided for high cost items.
Any large one-time purchases, such as large equipment requests, must
be accommodated within these limits.
 
CONSORTIUM/CONTRACTUAL COSTS - If collaborations or subcontracts are
involved that require transfer of funds from the grantee to other
institutions, it is necessary to establish formal subcontract
agreements with each collaborating institution.  A letter of intent
from each collaborating institution should be submitted with the
application.  Only the percentage of the consortium/contractual TOTAL
COSTS (direct and indirect) relative to the total DIRECT COSTS of the
overall project needs to be stated at this time. The following
example should be used to indicate the percentage cost of the
consortium, "The consortium agreement represents 27% of overall
$175,000 direct costs requested in the first year.".  A budget
justification for the consortium should be provided as described in
the "Budget Justification" section above (no Form Page 5 required for
the consortium).  Please indicate whether the consortium will be in
place for the entire project period and identify any future year
changes in the percentage relative to the parent grant.
 
If there is a possibility for an award, the applicant will be
requested to identify actual direct and indirect costs for all years
of the consortium.  Please note that total subcontract costs need not
be calculated in $25,000 modules.  However, when subcontract funds
are added to the parent grant budget, the total direct cost amount
must be included in the number of $25,000 modules requested.
 
BIOGRAPHICAL SKETCH - A biographical sketch is required for all key
personnel, following the modified instructions below.  Do not exceed
the two-page limit for each person.
- Complete the educational block at the top of the form page; - List
current position(s) and those previous positions directly relevant to
the application;
- List selected peer-reviewed publications directly relevant to the
proposed project, with full citation;
- The applicant has the option to provide information on research
projects completed and/or research grants participated in during the
last five years that are relevant to the proposed project.
 
OTHER SUPPORT - Do not complete the "Other Support" pages (Form Page
7).  Selected other support information relevant to the proposed
research may be included in the Biographical Sketch as indicated
above.  Complete Other Support information will be requested by NHLBI
staff if there is a possibility for an award.
 
CHECKLIST - No "Checklist" page is required as part of the initial
application.  A completed Checklist will be requested by NHLBI staff
if there is a possibility for an award.
 
The applicant should provide the name and phone number of the
individual to contact concerning fiscal and administrative issues if
additional information is necessary following the initial review.
 
Sample budgets and justification page will be provided upon request
or following the submission of a letter of intent.
 
Applications not conforming to these guidelines will be considered
unresponsive to this RFA and will be returned without further review.
 
Applicants from institutions that have a General Clinical Research
Center (GCRC) funded by the NIH National Center for Research
Resources may wish to identify the GCRC as a resource for conducting
the proposed research.  If so, a letter of agreement from either the
GCRC program director or principal investigator could be included
with the application.
 
The RFA label available in the PHS 398 (rev. 5/95) application form
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 and number must be typed on
line 2 of the face page of the application form and the YES box must
be marked.
 
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
6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for courier/overnight service)
 
Send an additional two copies of the application to the Chief, Review
Branch at the address listed under LETTER OF INTENT.  It is important
to send these two copies at the same time as the original and three
copies are sent to the Division of Research Grants.  Otherwise the
NHLBI cannot guarantee that the application will be reviewed in
competition for this RFA.
 
Applications must be received by October 25, 1996.  If an application
is received after that date, it will be returned to the applicant
without review.  The Division of Research Grants (DRG) will not
accept any application in response to this RFA that is essentially
the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The DRG will not accept
any application that is essentially the same as one already reviewed.
This does not preclude the submission of substantial revisions of
applications already reviewed, but such applications must include an
introduction addressing the previous critique.
 
REVIEW CONSIDERATIONS
 
Upon receipt, applications will be reviewed for completeness by the
DRG and responsiveness by the NHLBI and NIDDK.  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.  As part of the initial merit review, a
process 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 the evaluation of scientific merit of each
application will be similar to those used in the review of
traditional research-project grant applications, including novelty,
originality, and feasibilty of the approach; the training experience
and research competence of the investigator(s); the adequacy of the
experimental design; the suitability of the facilities; and the
appropriateness of the requested budget to the work proposed.
 
The initial review group will also examine the provisions for the
protection of human and animal subjects and the safety of the
research environment.
 
The personnel category will be reviewed for appropriate staffing
based on the requested percent effort.  The direct costs budget
request will be reviewed for consistency with the proposed methods
and specific aims.  Any budgetary adjustments recommended by the
reviewers will be in $25,000 modules.  The duration of support will
be reviewed to determine if it is appropriate to ensure successful
completion of the requested scope of the project.
 
AWARD CRITERIA
 
The anticipated date of award is August 1997.  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.
 
INQUIRIES
 
Inquiries concerning this RFA are encouraged.  Potential applicants
should request a copy of the full RFA, which will include sample
budget pages as previously stated.  The opportunity to clarify any
issues or questions from potential applicants is welcome.
 
Inquiries regarding programmatic issues may be directed to:
 
Dr. Helena O. Mishoe
Division of Blood Diseases and Resources
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, Room 10156
Bethesda, MD  20892-7950
Telephone:  (301) 435-0050
FAX:  (301) 480-0868
Email:  hm31y@nih.gov
 
Dr. David Badman
Division of Kidney, Urology, and Hematologic Diseases
National Institute of Diabetes and Digestive and Kidney Diseases
Natcher Building, Room 6AS-13C
45 Center Drive MSC 6600
Bethesda, MD  20892-6600
Telephone:  (301) 594-7717
FAX:  (301) 480-3510
Email:  badmand@ep.niddk.nih.gov
 
Direct inquiries regarding fiscal matters to:
 
Ms. Jane R. Davis
Grants Management Office
National Heart, Lung, and Blood Institute
6701 Rockledge Drive, MSC 7926
Bethesda, MD  20892-7926
Telephone:  (301) 435-0166
FAX:  (301) 480-3310
Email:  jane_davis@nih.gov
 
Trude Hillard
Division of Extramural Activities
National Institute of Diabetes and Digestive and Kidney Diseases 45
Center Drive, Room 6AN-44J, MSC 6600
Bethesda  MD  20892-6600
Telephone:  (301) 594-8859
Email:  HillardT@ep.niddk.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 number
93.839. Awards will be made under the authority of the Public Health
Service Act, Section 301 (42 USC 241) and administered under PHS
grant policies and Federal regulations, most specifically 42 CFR Part
52 and 45 CFR Part 74.  This program is not subject to the
intergovernmental review requirements of Executive Order 12372, or to
Health Systems Agency Review.
 
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.
 
References
 
1.  Sieff, CA:  Hemopoietic growth factors.  J. Clin. Invest.
79:1549, 1987.
 
2.  Torok-Storb, B:  Cellular interactions.  Blood 72:373, 1988.
 
3.  Dainiak, N:  Surface membrane-associated regulation of cell
assembly, differentiation, and growth.  Blood 78:269, 1991.
 
4.  Tavassoli, M, Hardy, C:  Molecular basis of homing of
intravenously transplanted cells to the marrow.  Blood 76:1059, 1990.
 
5.  Witte, ON:  Steel locus defines new multipotent growth factors.
Cell 63:5, 1990.
 
6.  Liesveld, JL, Winslow, JM, Kempski, MC, Ryan, DH, Brennan, JK,
Abboud, CAN:  Adhesive interactions of normal and leukemic CD34+
myeloid/progenitors:  Role of marrow stromal, fibroblast and
cytomatrix components.  Exp. Hematol. 19:63, 1991.
 
7.  Brandt, J, Srour, E, Besien, K, Briddell, RA, Hoffman, R:
Cytokine-dependent long term culture of highly purified precursors of
hematopoietic progenitor cells from human bone marrow.  J. Clin.
Invest. 86:932, 1990.
 
8. Spangrude, GJ, Heinifeld, S, Weissman, IL:  Purification and
characterization of mouse hematopoietic stem cells.  Science 240:58,
1988.
 
.

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