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) 710-0267. 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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