SPECIALIZED CENTERS OF RESEARCH (SCOR) IN HEMATOPOIETIC STEM CELL BIOLOGY Release Date: August 16, 1999 RFA: HL-99-021 National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: December 1, 1999 Application Receipt Date: January 14, 2000 PURPOSE This solicitation invites grant applications to enter a single open competition for Specialized Centers of Research (SCOR) in Hematopoietic Stem Cell Biology. The goal of this initiative is 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 expansion, gene insertion and expression, 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 initiative, 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 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit institutions, public and private, such as universities, colleges, hospitals, and laboratories. This RFA is intended to support SCOR grants for basic and clinical investigations. Applications that include only basic or only clinical research will not be responsive to this RFA. In addition, clinical research projects focused on large epidemiologic studies or large clinical trials will be considered unresponsive to this RFA. Foreign institutions are ineligible from receiving awards under this solicitation. 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 as Principal Investigators or responsible project investigators. 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 determined non-competitive, the over all 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 Institutes of Health (NIH) specialized centers (P50) mechanism to support this research program. Responsibility for planning the proposed project will be solely that of the applicant. The total project period for applications submitted in response to the present RFA may not exceed five years. The anticipated start date of award is September 30, 2000. Although multidisciplinary approaches are required, it is not the intent of this RFA to solicit applications for large clinical trials or large epidemiologic studies. In general, funds will not be provided for the purchase and installation of expensive, new equipment. Upon initiation of the program, there will be required communications between SCORs, usually in the setting of a biennial combined meeting of SCOR participants. Applicants should request travel funds for this purpose in fiscal years 2001, 2003, and 2005 of the budget. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. Basic and Clinical Research The overall concept of a SCOR program focuses on scientific issues related to diseases relevant to the mission of the National Heart, Lung, and Blood, Institute (NHLBI). It is essential, therefore, that all applications include both basic and clinical research projects. 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, which is defined as research conducted with human patients/subjects or on material of human origin such as tissue or other specimens for which an investigator directly interacts with 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 epidemiologic 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. Length 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. 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 SCOR program in Hematopoietic Stem Cell Biology is in the initial five-year project period and this competition is for the second five-year competition. The comprehensive evaluation of this SCOR Program will be conducted during the second project period according to the following timetable. Announcement of SCOR renewal competition FY 1999 Project Period (second competition) FY 2000 to FY 2004 Letters to SCOR Directors regarding FY 2001 (mid-way through year 02 SCOR evaluation plans of the 2nd project period) SCOR Evaluation Meeting FY 2001 (late in year 02 of 2nd project period) Notification of SCOR Directors of FY 2002 (mid-way through year 03 NHLBI decision of 2nd project period) 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. 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 and can provide scientific expertise in areas and topics that may not be readily available at the applicant institution. However, the consortium projects must not constitute greater than 50 percent of the proposed projects. It is also imperative that a consortium application be prepared so that the programmatic, fiscal, and administrative considerations are explained fully. Applicants 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 the group at the parent institution. Facilities and Administrative costs paid as part of a consortium agreement are excluded from the limit on the amount of direct costs that can be requested. 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 Operation Branch, NHLBI, (301) 435-0166. FUNDS AVAILABLE Applicants may request up to $1,220,000 in direct costs, not including Facilities and Administrative costs for collaborating institutions, in the first year. Competing renewal applicants may request an increase in their budget in the first competing year (Year 06), not to exceed 10 percent of the costs awarded in the last noncompeting award year (Year 05) or $1,220,000, whichever is greater (excluding Facilities and Administrative costs on subcontracts). Applicants may request up to a three percent increase for subsequent noncompeting years. The specific number to be funded will, however, depend on the merit and scope of the applications received and on the availability of funds. Award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. Designated funding levels are subject to change at any time prior to final award, due to unforeseen budgetary, administrative, and/or scientific developments. 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 justification. Final decisions will depend on the nature of the justification and the availability of funds. RESEARCH OBJECTIVES Background The production of blood cells, or hematopoiesis, takes place in the bone marrow. Among the billions of cells in the bone marrow, there is a very small subpopulation that has a pivotal role in the maintenance of hematopoiesis. This subpopulation is composed of hematopoietic stem cells (HSC) that, with their distinctive capabilities of self-renewal and differentiation, furnish a constant supply of blood cells of all hematopoietic lineages throughout life. Thus, 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 which 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 of 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 which 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, have 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. Stem cell transplantation (SCT) has achieved significant therapeutic success over the last 10 years, providing a viable treatment option for many previously incurable diseases. However, several inherent limitations of the procedure have restricted its widespread use. These include: lack of sufficient donors for all recipients, a period of bone marrow (BM) aplasia leading to severe, prolonged neutropenia and thrombocytopenia, and the potential for tumor contamination in autologous SCT. Continued research efforts to address these limitation are needed. Recent studies suggest that cord blood transplantation may help eliminate the issue of donor availability and some post-transplant complications (1). Recent Advances in Basic/Clinical Science STEM CELL IDENTIFICATION AND EXPANSION Considerable progress has been made in purifying primitive cell populations by cell sorting based on the absence or presence of cell-surface markers (2). Characterization of specific sorted fractions for stem-cell function is currently based on CD34, a cell-surface sialomucin-like adhesion molecule that is expressed on 1-3 percent of bone marrow cells. CD34 is not unique to stem cells, as it is also detected on clonogenic progenitors and some lineage committed cells (3). CD34 has been used as a convenient positive selection marker to enrich HSC used in stem cell transplantation and gene therapy. However, new findings (4) have added to the growing evidence (5,6) that some stem cells in the bone marrow do not express CD34. The importance of CD34- negative HSC for human stem cell transplantation is currently unclear. The identification of a marker for positive selection of CD34-negative HSC will allow further characterization and quantitative analysis by comparison of the in vivo long-term marrow repopulating ability of CD34-positive and CD34- negative cells. Clearly, the most appropriate cell population for transplantation is an extremely important issue. Research efforts to extensively characterize the human HSC and to clarify the significance of the CD34-negative cell population are important to pursue. Identification of conditions for optimizing the expansion of different subsets of primitive cells from various sources has important implications for clinical transplantation and gene transfer. Currently, this novel domain of cellular therapy aims to generate stem and progenitor cells, as well as more differentiated post-progenitor cells and antigen-presenting dendritic cells. Recently, a number of laboratories have shown that both early and delayed phases of engraftment are mediated by PHSC within a graft and that engraftment can be accelerated by transplanting greater numbers of PHSC. Thus, increasing efforts have been directed, towards developing methods to expand PHSC ex vivo. The clinical usefulness of ex vivo generated cells needs to be established. Identification of the Refinement of cell-based culture systems and elucidation of the molecular events which permit the ex vivo expansion of hematopoietic stem and progenitor cells from various sources is extremely important to pursue. STEM CELL MICROENVIRONMENT The complex processes of erythropoiesis, myelopoiesis, megakaryopoiesis, and lymphopoiesis are regulated both positively and negatively by the bone marrow microenvironment. The bone marrow stromal microenvironment, itself a connective tissue, is composed of adipocytes, macrophages, endothelial cells, and mesenchymal progenitor cells. The stromal cells appear to be derived from a pluripotent cell located in the marrow, often referred to as a mesenchymal progenitor cell, which is believed to be distinct from the hematopoietic stem cell. Recent laboratory-based evidence now suggests that the combination of hematopoietic stem cells and bone marrow stromal cells may be required for maximal engraftment and self renewal of transplanted cells. In addition, preliminary data suggest that marrow stromal cells modulate graft-vs-host- disease (GVHD). Thus, there is a particular concentrated effort needed for new strategies to optimize stem cell engraftment. It is important to assess the use of mesenchymal cells (1) to enhance engraftment rate and quality after transplant, (2) to serve as vehicles for delivery of exogenous gene products, (3) to provide repair of mesenchymal origin tissues, and (4) to facilitate prevention and treatment of GVHD. A combined stem and stromal cell strategy will potentially maximize engraftment and vastly improve therapeutic outcomes. GENE THERAPY 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. 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. Studies have demonstrated that retroviral-mediated gene transfer into HSCs is feasible and safe. However, currently available HSC gene-transfer protocols do not reliably transfer genes into HSCs with long-term repopulating capacity. A greater understanding of the basic biology of retroviruses and hematopoiesis will enhance the development of more advanced and efficient HSC retroviral vector delivery systems. Successful HSC gene transfer approaches will need to develop methods of targeting nondividing HSCs and/or stimulating HSCs to proliferate prior to transduction. New generation of vectors may permit the inclusion of larger genes, transcriptional regulatory units, tissue specific expression, and multiple genes and allow the insertion of viral genes into site-specific genomic locations. Recent success in the use of gene therapy for the treatment of AIDS and hemophilia B has been reported. Dowdy and colleagues (7) report the use of gene therapy to kill HIV as a potential alternative to highly active antiretroviral therapy (HAART). In addition, encouraging progress in the treatment of hemophilia B with gene therapy was recently demonstrated. High and colleagues (8) have developed an adeno-associated viral (AAV) vector that is able to deliver the canine factor IX gene to hemophiliac dogs. the researchers recorded a constant, but low level production of factor IX in the dogs for 16 months. Consistent with these results, Kay and colleagues (9) have developed a similar vector that they injected into the portal vein of the liver in hemophiliac dogs and recorded factor IX production for eight months. The ability to treat hemophiliac animals is a major step forward towards human clinical trials. These results support the potential use 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. Important research needs exist for improved vector systems and understanding the biology of hematopoietic stem cell gene transfer to achievement efficient, stable and long-term genetic correction of hematopoietic stem and progenitor cells and their mature progeny. 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, by homologous replacement with the cloned wild-type allele, or by 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 to the large numbers of patients with various forms of thalassemia and sickle cell anemia who must now struggle with incomplete therapies. Proposed Research 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 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. Examples of Areas to be Addressed by this Initiative: 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 Novel markers for stem cell identification to enhance isolation and purification. and ex vivo stem cell expansion from a variety of sources. o Refinement of cell-based culture systems and elucidation of the molecular events which permit ex vivo expansion of hematopoietic stem cells from a variety of sources. o Identification and characterization of functional, molecular regulators of stem cell self-renewal and commitment. o In vivo and in vitro assay systems for human stem cells. o Role of growth factors, cytokines, receptors, transmembrane signaling, marrow stroma and microenvironment, and adhesive proteins in stem cell interactions and hematopoiesis. o Identification and characterization of stromal cells which maximize stem cell engraftment. 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 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 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. SPECIAL REQUIREMENTS Special features of SCOR grants are: o They provide opportunities for investigators with mutual or complementary interests to engage in multidisciplinary basic and clinical research in a synergistic fashion such that major therapeutic advances will be realized. o A SCOR has a central theme to which all research projects pertain. In addition, a SCOR may include core units to provide services to the various research projects and to support the organizational and administrative aspects of the program. o Inherent in the SCOR program is a special interaction between the SCOR director, the grantee institution and the Division of Blood Diseases and Resources (DBDR). Upon initiation of the program, DBDR will hold periodic meetings to encourage exchange of information among investigators who participate in this program and to stimulate collaboration. Applicants should include 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. o The Division's overall SCOR program and each SCOR grant undergo periodic evaluation. The progress reports are prepared for the information of the National Heart, Lung, and Blood Advisory Council, the Division of Blood Diseases and Resources staff, and ad hoc members of SCOR evaluation groups. Requirements of SCOR grants: o Research conducted at the individual centers must include both basic and clinical research to ensure that advances in the basic sciences are translated rapidly into clinical applications and that clinical needs will provide a direction for the basic research. Therefore, each SCOR grant application and award must include one or more research projects involving human patients/subjects. The basic research projects should clearly relate to the disease focus and contribute to elucidation of mechanisms underlying the disease, or to improved diagnosis or management of the disease. o Each component project requires a well-described hypothesis, preliminary data and a time-table for conducting the proposed investigations. o If core facilities are included, the relationship of each component project to each core should be described. o The principal investigator should be an established 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. o Project leaders must agree to commit at least 20 percent effort to each project for which they are responsible. Investigators with minimal research experience, but promising credentials, may participate; however, it is expected that most of the project directors will be investigators with significant research experience. o Each SCOR must have a well-delineated organizational structure and administrative mechanism that foster interactions between investigators, accelerate the pace of research, and ensure a productive research effort. o If a project director transfers to another institution, support for the project will normally not be continued as a consortium. Because of the size and complexity of a SCOR, prospective applicants are urged to consult with the staff of the Division of Blood Diseases and Resources early in the preparation of the application (see Inquiries section). 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). 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 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 under Inquiries. Program staff may also provide additional relevant information concerning the policy. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects" that was published in the NIH Guide for Grants Contracts, March 6, 1998, and is available at the following URL address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html. LETTER OF INTENT Prospective applicants are asked to submit, by December 1, 1999, 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, it assists the 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: Dr. C. James Scheirer Division of Extramural Affairs National Heart, Lung and Blood Institute 6701 Rockledge Drive, Suite 7216, MSC 7924 Bethesda, MD 20892-7924 Telephone: (301) 435-0266 FAX: (301) 480-3541 Email: js110j@nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional business offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910; telephone: (301) 710-0267; Email: GrantsInfo@nih.gov, and from the NHLBI program administrator listed under Inquiries. Specific instructions for preparing a SCOR application are also available from the program contact listed under INQUIRIES. The RFA label included in grant application PHS 398 (rev. 4/98) 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, SCOR in Hematopoietic Stem Cell Biology and number, HL-99-021 must be typed on line 2 of the face page of the application form and the AYES@ box must be marked. The RFA label and line 2 of the application should both indicate the RFA number. The sample RFA label available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Send or deliver a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent 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 Center for Scientific Review (CSR); otherwise the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applications must be received by January 14, 2000. If an application is received after that date, it will be returned to the applicant without review. The CSR 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 CSR 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 CSR and responsiveness by the NHLBI staff. 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. Applicants should submit the highest quality applications possible to CSR as no site visits or reverse site visits will be held. As part of the initial merit review, a streamlined process may be used by the initial review group in which applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level of review by the National Heart, Lung, and Blood Advisory Council. Review Criteria 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. o Appropriateness of the central theme and coordination and interrelation of the research projects and core units. AWARD CRITERIA The anticipated date of award is September 30, 2000 (FY 2000) for the SCORS in Hematopoietic Stem Cell Biology. Awards will be made according to priority score, availability of funds, and programmatic priorities. INQUIRIES Written and telephone inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues and requests for supplemental instructions to: Charles M. Peterson, M.D. Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Suite 10018, MSC 7950 Bethesda, MD 20892-7950 Telephone: (301) 435-0050 FAX: (301) 480-0868 Email: petersoc@nih.gov Direct inquiries regarding fiscal and administrative matters to: Ms.Jane Davis Division of Extramural Affairs National Heart, Lung and Blood Institute 6701 Rockledge Drive, Suite 7174, MSC 7926 Bethesda, MD 20892-7926 Tel: (301)-435-0166 FAX: (301)-480-3310 Email: davisj@nih.gov 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 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.
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