Full Text HL-94-010 SPECIALIZED CENTERS OF RESEARCH IN HEMATOPOIETIC STEM CELL BIOLOGY NIH GUIDE, Volume 23, Number 14, April 8, 1994 RFA: HL-94-010 P.T. Keywords: National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: May 31, 1994 Application Receipt Date: September 15, 1994 PURPOSE The objectives of this program are to advance our knowledge of basic stem cell biology in areas of stem cell isolation, quantitation by in vivo assay, in vitro and in vivo growth and replication, gene insertion, and engraftment. This basic knowledge will be applied clinically to enhance our ability to achieve successful hematopoietic stem cell therapy to cure both genetic and acquired diseases and to perform successful gene therapy using the hematopoietic stem cell as the target for gene transfection and for life-long expression of normal genes. 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 Request for Applications (RFA), Specialized Centers of Research (SCOR) in Hematopoietic Stem Cell Biology, 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. 017-001-00473-01) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by for-profit and non-profit domestic institutions, public and private, such as universities, colleges, hospitals, and laboratories. This RFA is intended to support SCOR grants for basic and clinical investigations. Therefore, applications that include only basic or only clinical research will not be responsive to this announcement. In addition, clinical research projects focused on large epidemiologic studies or large clinical trials will be considered unresponsive to this RFA. Awards will not be made to foreign institutions. However, under exceptional circumstances, a foreign component critical to a project may be included as a part of that project. Women and minority investigators are encouraged to apply. The Principal Investigator should be an established research scientist with the ability to ensure quality control and the experience to administer effectively and integrate all components of the program. A minimum time commitment of 25 percent is expected for this individual. The Principal Investigator must also be the project leader of one of the component research projects. If, through peer review, this project is not recommended for further consideration, the overall SCOR application will not be considered further. If this project is judged by peer review to be of low scientific merit, it will markedly reduce the overall scientific merit ranking assigned to the entire application by the review committee. Project leaders must agree to commit at least 20 percent effort to each project for which they are responsible. MECHANISM OF SUPPORT This RFA will use the National Heart, Lung, and Blood Institute (NHLBI) SCOR (P50) grant to support this research program. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. Basic and Clinical Research The overall concept of a SCOR program focuses on scientific issues related to the mission of the NHLBI. It is essential, therefore, that all applications include both basic and clinical research. Interactions between basic and clinical scientists are expected to strengthen the research, enhance transfer of fundamental research findings to the clinical setting, and identify new research directions. Plans for transfer of findings from basic to clinical studies should be described. Each SCOR grant application and award must include research involving human patients/subjects. Support may be provided for human biomedical and behavioral studies of etiology, pathogenesis, prevention and prevention strategies, diagnostic approaches, and treatment of diseases, disorders, or conditions. Small population-based studies, where the research can be completed within five years, may also be proposed. In addition, basic research projects must be included that relate to the clinical focus. A SCOR may also contain one or more core units that support the research projects. Applications 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 the GCRC program director/principal investigator could be included with the application. Duration of SCOR Programs Each NHLBI SCOR program is limited to 10 years of support. Exceptions to this policy will be made only if a thorough evaluation of needs and opportunities, conducted by a committee composed of non-federal experts, determines that there are extraordinarily important reasons to continue a specific SCOR program. Thus, under this policy, a given SCOR grant is awarded for a five-year project period following an open competition. Only one five-year competing renewal is permitted, for a total of 10 years of support, unless the SCOR program is recommended for extension. The NHLBI comprehensive evaluation of the HEMATOPOIETIC STEM CELL BIOLOGY SCOR program will be conducted during the second project period according to the following timetable: Program Announced FY 1994 Project Period (First Competition) FY 1996 to FY 2000 Program Reannounced FY 1999 Project Period (Second Competition) FY 2001 to FY 2005 Letter to SCOR Directors FY 2002 (midway through regarding SCOR evaluation plans year 02 of 2nd project period) SCOR Evaluation Meeting FY 2003 (late in year 02 of 2nd project period) Notification of SCOR Directors FY 2003 (midway through of NHLBI Decision year 03 of 2nd project period) Number of Applications The NHLBI does not limit the number of SCOR applications in a given SCOR program from one institution provided there is a different SCOR principal investigator for each application and each application is self-contained and independent of the other(s). This does not preclude cooperation planned or possible among participants of SCORs after awards are made. Scientific overlap among applications will not be accepted. If more than one application is envisioned from an institution, the institution is encouraged to discuss its plans with the NHLBI SCOR Program Administrator. FUNDS AVAILABLE Applicants may request up to $1,125,000 in direct costs, not including indirect costs for collaborating institutions, in the first year with a maximum increase of no more than four percent in each additional year requested in the application. Award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. It is anticipated that at least two SCOR grants will be funded. NHLBI's FY 1996 plans for this initiative include a maximum of $4.4 million. The specific amount to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Equipment is included in the budget limitation. However, requests for expensive special equipment that cause an application to exceed this limit may be permitted on a case-by-case basis following staff consultation. Such equipment requires in-depth justification. Final decisions will depend on the nature of the justification and the Institute's fiscal situation. Consortium Arrangements If a grant application includes research activities that involve institutions other than the grantee institution, the program is considered a consortium effort. Such activities may be included in a SCOR grant application, but it is imperative that a consortium application be prepared so that the programmatic, fiscal, and administrative considerations are explained fully. The published policy governing consortia is available in the business offices of institutions that are eligible to receive Federal grants-in-aid. Consult the latest published policy governing consortia before developing the application. If clarification of the policy is needed, contact Ms. Jane Davis, Grants Operations Branch, NHLBI, 301-594-7436. Applicants of SCOR grants should exercise great diligence in preserving the interactions of the participants and the integration of the consortium project(s) with those of the parent institution, because synergism and cohesiveness can be diminished when projects are located outside of the group at the parent institution. Indirect costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. RESEARCH OBJECTIVES Background The production of blood cells, or hematopoiesis, takes place in the bone marrow. Hematopoiesis begins with the most primitive, pluripotent hematopoietic stem cell, which has a frequency of less than one per 10,000 nucleated bone marrow cells. The stem cell can either replicate and remain a stem cell or differentiate into myeloid or lymphoid stem cells, which in turn can further proliferate 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 or other cytokines that enhance cellular proliferation and maturation, as well as inhibitory activities that prevent proliferation. These activities are generated and act within the marrow microenvironment. Currently, allogeneic bone marrow transplants are recognized as a treatment of choice for chronic myelogenous leukemia, acute leukemias failing initial treatment, aplastic anemia, and several lethal disorders of the immune system and hematopoiesis. Allogeneic bone marrow transplantation has become increasingly used as a cure for a variety of genetic defects of the hematopoietic and immune systems, and for lipid storage diseases. Genetic diseases that have been successfully cured by bone marrow transplantation include Cooley's anemia, sickle cell anemia, severe combined immunodeficiency, Wiskott-Aldrich syndrome, Fanconi anemia, Blackfan-Diamond anemia, ataxia telangiectasia, infantile agranulocytosis, Chediak-Higashi disease, chronic mucocutaneous candidiasis, mucopolysaccharidosis, cartilage-hair hypoplasia, Gaucher's and other lipid storage diseases. Some of these diseases, such as Cooley's anemia (beta-thalassemia) and sickle cell anemia, are major worldwide public health problems. Others are devastating orphan diseases that are extremely costly to treat. Collectively, these genetic diseases occur in tens-of-thousands of births per year. It is also recognized that several malignant disorders are sensitive to agents that have, as their dose-limiting toxicity, myelo-ablation. This knowledge, along with the initial success of marrow and peripheral blood-derived autografts administered after myelo-ablative therapy, has clearly defined the rationale for the use of hematopoietic stem and progenitor cells in the treatment of several non-hematopoietic malignancies, including breast cancer, which occurs with alarming frequency. At present, over 5,000 HLA-matched marrow allografts are performed annually. Only about 35 percent of transplant candidates have a suitably matched sibling marrow donor. However, the development of a national registry of volunteer marrow donors (National Marrow Donor Program) and improvements in histocompatibility testing have provided the alternative of marrow transplants from unrelated donors. About 40 percent of patients who activate or formalize their searches for an unrelated donor are now able to be transplanted. Hence, about 60 percent of patients with transplantable disorders are able to get a transplant. The significant cost of the procedure, which could be as much as $200,000 not including the possible long-term care for chronic graft-versus-host disease, may preclude many from benefiting from this form of treatment. Recent Advances in Basic Science Over the past five years, research into the biology of hematopoiesis in animal models and in man have led to significant advances in the phenotypic and functional characterization of stem cells. We have recently seen improvements in stem cell purification and in vitro expansion (1,2). These observations have increased our appreciation of the complexity of the genetic and cellular events required for homing, engraftment, growth, and development of stem cells within an allogeneic or autologous microenvironment. The advent of new molecular technology that allows analysis of gene expression in small numbers of cells makes it possible finally to address molecular events associated with stem cell function. A multitude of cloned and purified hematopoietic growth factors and cytokines are now available to facilitate stem cell research. In most cases, receptors for these activities have also been cloned, and studies are underway to define intracellular signaling pathways. Additionally, interacting accessory cells have been identified that, in concert with cytokines, may regulate or promote stem cell growth, self-renewal, and differentiation. Progress in the ability to define and isolate functional subsets of these marrow stromal cells provides an opportunity to control regulatory events in the marrow. Advances in these areas have served to spark an interest in the application of modern cellular and molecular biological techniques to the study of stem cells. Many of these areas are now ready for investigation. Gene Therapy Progress in the gene therapy area may no longer be impeded for lack of purified populations of stem cells, which are the ideal target for gene transfer. They can be easily obtained, manipulated in vitro, reinfused into a patient, and are capable of repopulating the bone marrow. Theoretically, if appropriately manipulated, they will self-renew, differentiate, and express the inserted normal gene for the life of the patient. Precisely how to manipulate the stem cell to achieve efficient gene transfer without compromising the functional potential required for long-term hematopoiesis remains a critical area of research. Nevertheless, the success of whole marrow transplantation for the correction of several genetic disorders has focused attention on the hematopoietic stem cell as a target for gene therapy for the correction of several genetic disorders of hematopoiesis and metabolism. While encouraging results have already been achieved with infusions of genetically modified autologous lymphocytes for the correction of immune function in children with ADA-deficient SCID, there remain major obstacles to the achievement of efficient, stable, and long-term genetic correction of marrow stem and progenitor cells and their mature progeny. Nevertheless, these early results signal the potential of this approach for correction of a variety of genetic disorders, such as thalassemia, Fanconi anemia, Sickle cell anemia, lethal genetic disorders of immunity, and potentially severe autoimmune disorders and diseases of metabolism. Stem Cell Therapy Research in hematopoietic stem and progenitor cells has brought about a new and fascinating therapeutic opportunity. The advances described above should permit more widespread application of stem cell enriched transplants for genetic and acquired diseases in both children and adults. The congenital and acquired marrow failure and dysfunction syndromes may soon be swiftly and completely treated by the infusion of autologous stem cells rendered normal by gene insertion, homologous replacement with the cloned wild-type allele, or the transplantation of foreign normal stem cells rendered compatible by manipulations of surface antigens. This exciting prospect, which will massively reduce the overwhelming cost and inefficient efforts to maintain the lives of afflicted patients, will finally offer a definitive cure for patients with rare disorders of marrow function such as those with Fanconi's Anemia, Wiskott-Aldrich syndrome, and Kostmann syndrome. It will also offer real hope to patients with acquired aplastic anemia and the large numbers of patients with various forms of thalassemia and sickle cell anemia who must now struggle with incomplete therapies. Recent studies indicate that either allogeneic donors or genetically modified autologous marrow stem cell grafts may also be used to correct several disorders in utero, early in the course of embryonal development. In animal models (3) and in humans (4,5) donor fetal liver hematopoietic stem cells can also be transplanted with varying degrees of success into an unrelated pre-immune recipient fetus. These procedures have been performed without tissue matching, without marrow ablation, without immunosuppressive drugs, and without the development of graft-versus-host disease. This suggests that the fetus is both an ideal recipient and donor of hematopoietic stem cells. Other Areas We are now in an excellent position to make significant progress in other areas that are of importance to stem cell therapy. For example, the recent intriguing report (6) of a single cell capable of reconstituting the bone marrow stroma and multilineage hematopoiesis has potential major implications and is in need of extensive investigation. Additional areas include the interaction of stem cells with adhesive proteins in the marrow stroma, the manipulation and enhancement of the stem cell homing receptor (7), and research on alternate sources of hematopoietic stem cells such as fetal liver (3-5), cord blood (8), and peripheral blood (9). The SCOR as a Mechanism for Supporting Stem Cell Biology Research A spectrum of research, ranging from basic molecular and cellular biology through clinical applications of this newly acquired knowledge, is now feasible. Stem cell biology research is ideally suited to a multidisciplinary approach. The collaboration of molecular and cell biologists, hematologists, immunologists, transplantation biologists, and clinicians will not only enhance, but is probably required for, the transfer of landmark advances in basic research into clinical applications. The SCOR mechanism may facilitate the development of skilled multidisciplinary teams. The SCOR mechanism is uniquely designed to support this spectrum of multidisciplinary basic and clinical research in a synergistic fashion such that major therapeutic advances will be realized in the next decade in both gene therapy and stem cell transplantation. Areas to be Addressed by this Initiative include, but are not limited to: o Basic stem and progenitor cell biology, evaluating a variety of sources including marrow, peripheral blood, cord blood, fetal liver, and embryonic stem cells. o Stem cell identification, isolation, purification, and in vitro (ex vivo) expansion. o In vivo and in vitro assay systems for human stem cells. o Manipulation of stem cell self-renewal and commitment. o Role of growth factors, cytokines, receptors, transmembrane signaling, marrow stroma and microenvironment, and adhesive proteins in stem cell interactions and hematopoiesis. o Interaction of stem cells and stromal cells with viruses such as parvovirus, HIV, and CMV. o Stem cell transplantation and expression in animal models. o Histocompatibility and allo-interactions, mechanism of induction of transplant tolerance, minimizing the GVH effect and graft rejection, and maximizing the graft versus leukemia effect. o Enhancing stem cell engraftment through manipulation of stem and progenitor cell homing receptors in the marrow stroma and on stem cell surfaces. o Stem cell therapy to correct genetic diseases and congenital and acquired marrow dysfunction. o Gene therapy using hematopoietic stem cells as targets for gene insertion and long term expression of normal genes, using retroviral vectors, adeno-associated viral vectors, and other sources of gene transduction. The primary focus of the overall SCOR grant application should be on non-malignant hematologic diseases. Biennial Research Meetings Upon initiation of the program, the NHLBI will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program and to stimulate collaboration. Applicants should request additional travel funds for a two-day meeting every other year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. STUDY POPULATIONS 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 9, 1994 (FR 59 11146-11151) 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. LETTER OF INTENT Prospective applicants are asked to submit, by May 31, 1994, 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. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains is helpful in planning for the review of applications. It allows NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: Chief, Review Branch Division of Extramural Affairs National Heart, Lung and Blood Institute Westwood Building, Room 557A Bethesda, MD 20892 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301-435-0714. The RFA label available in the PHS 398 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, to identify the application as a response to this RFA, check "YES", enter the title "Specialized Centers of Research in Hematopoietic Stem Cell Biology" and the RFA number HL-94-010 on line 2a of the face page of the application. Send or deliver a signed, typewritten original of the application, including the checklist, and three signed photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Send two additional 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 September 15, 1994. If an application is received after that date, it will be returned to the applicant. DRG will not accept any application in response to this announcement that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. 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 by NIH staff for completeness and responsiveness. Incomplete applications or applications deemed not responsive to the RFA will be returned to the applicant without further consideration. Crucial to the initial scientific review will be a triage process that will eliminate all applications that are deemed not scientifically competitive within the goals and criteria of the RFA. Those applications that are complete, responsive, and competitive will be further evaluated for scientific and technical merit by an appropriate peer review group convened by the NHLBI. The second level of review will be provided by the National Heart, Lung, Blood Advisory Council. Factors to be considered in the evaluation of each application will be similar to those used in review of traditional research grant applications and, in addition, will include overall proposed interactions among basic and clinical research projects. Major factors to be considered in the evaluation of applications include: o Scientific merit of the proposed basic and clinical research projects including significance, importance, and appropriateness of the theme; innovation, originality, and feasibility of the approach; and adequacy of the experimental design. o Leadership, scientific stature, and commitment of the program director; competence of the investigators to accomplish the proposed research goals and their time commitment to the program; and the feasibility and strength of consortium arrangements. o Collaborative interaction among basic and clinical research components, the balance between them, and plans for transfer of potential findings from basic to clinical studies. o Adequacy of the environment for performance of the proposed research including clinical populations and/or specimens; laboratory facilities; proposed instrumentation; quality controls; administrative structure; institutional commitment; and, when needed, data management systems. o Appropriateness of the budget for the proposed program. AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program needs and balances, and the availability of funds. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Special supplemental instructions for the preparation of large, multi-project grant applications for the NHLBI can be obtained by contacting the Stem Cell Biology SCOR Program Administrator, as indicated below. Direct inquiries regarding scientific issues to: Alan S. Levine, 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 Direct inquiries regarding fiscal and administrative matters to: Ms. Jane Davis Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A15C Bethesda, MD 20892 Telephone: (301) 594-7436 FAX: (301) 594-7492 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.839, Blood Diseases and Resources. Awards will be made under the 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 requirement of Executive Order 12372 or Health Systems Agency review. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. 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. REFERENCES 1. Spangrude GJ, Heinifeld S, Weissman IL: Purification and characterization of mouse hematopoietic stem cells. Science 240:58, 1988. 2. 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. 3. Harrison MR, Slotnick RN, Crombleholm TM, et al: In utero transplantation of fetal liver haematopoietic stem cells in monkeys. Lancet 2:1425, 1989. 4. Raudrant D, Touraine JL, Rebaud A: In utero transplantation of stem cells in humans: technical aspects and clinical experience during pregnancy. Bone Marrow Transplantation 9(suppl 1):98, 1992. 5. Touraine JL, Raudrant D, Rebaud A, et al: In utero transplantation of stem cells in humans: immunological aspects and clinical follow-up of patients. Bone Marrow Transplantation 9(suppl 1):121, 1992. 6. Huang S, Terstappen LWMM: Formation of haematopoietic microenvironment and haematopoietic stem cells from single human bone marrow stem cells. Nature 360:745-749, 1992. 7. Tavassoli M, Hardy C: Molecular basis of homing of intravenously transplanted cells to the marrow. Blood 76:1059, 1990. 8. Gluckman E, Broxmeyer HE, Auerbach AD, et al. Hematopoietic reconstitution in a Fanconi's anemia patient by means of umbilical cord blood from an HLA-identical sibling. New Engl J Med 321:1174-1178, 1989. 9. Kessinger A, Armitage JO. The evolving role of autologous peripheral stem cell transplantation following high-dose therapy for malignancies (Editorial). Blood 77:211-212, 1991. .
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