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 301/710-0267, 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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