Full Text AI-95-009 IMMUNOPATHOGENESIS OF CHRONIC GRAFT REJECTION NIH GUIDE, Volume 24, Number 3, January 27, 1995 RFA: AI-95-009 P.T. 34 Keywords: Pathogenesis Immunology Immunosuppression Transplantation of Organs Biology, Cellular National Institute of Allergy and Infectious Diseases Letter of Intent Receipt Date: July 1, 1995 Application Receipt Date: October 17, 1995 APPLICATIONS IN RESPONSE TO THIS REQUEST FOR APPLICATIONS (RFA) MUST BE PREPARED USING A MODIFIED (ABBREVIATED) GRANT APPLICATION FORMAT; SPECIFIC INSTRUCTIONS FOR COMPLETING THE APPLICATION ARE IN A BROCHURE ENTITLED "INSTRUCTIONS FOR ABBREVIATED APPLICATIONS FOR PROGRAM PROJECT (P01) GRANTS IN RESPONSE TO RFA AI-95-009, IMMUNOPATHOGENESIS OF CHRONIC GRAFT REJECTION" AVAILABLE FROM NIAID STAFF IDENTIFIED UNDER INQUIRIES. PURPOSE The Division of Allergy, Immunology and Transplantation of the National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), invites applications for program projects in the immunopathogenesis of chronic graft rejection to evaluate the immune response to organ allografts, to elucidate the important cellular and molecular events of both the induction and effector phases of chronic solid organ graft rejection, and to develop improved therapeutic approaches to enhance long-term graft survival. Collaboration between basic scientists and clinical investigators is encouraged. 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 RFA, Immunopathogenesis of Chronic Graft Rejection, is related to the priority area of clinical prevention services. 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 Research grant applications may be submitted by domestic for-profit and non-profit organizations, public and private institutions, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign organizations are not eligible to apply. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The mechanism of support will be the program project (P01) grant. This mechanism supports broadly based multidisciplinary research programs that have a well-defined central research focus or objective. An important feature of the program project is that the interrelationships of the individual scientifically meritorious projects will result in a greater contribution to the overall program goals than if each project were pursued individually. The program project grant consists of a minimum of three interrelated individual research projects that contribute to the program objective. The program project grant also can provide support for certain common resources termed cores. Such resources should be utilized by two or more projects within the program project. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period may not exceed five years. At this time, the NIAID is administratively limiting the duration of P01 grants to four years; this administrative limitation may change in the future. The earliest anticipated award date is August 1996. FUNDS AVAILABLE The estimated total funds (direct and indirect) available for the first year of support for this RFA will be $1.5 million. In fiscal year 1996, the NIAID plans to fund approximately two program projects related to this RFA. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Applications may not request budgets in excess of $750,000 in total (direct and indirect) costs in the first year. NIH is currently limiting annual inflationary increases to no more than four percent for future years. The usual PHS policies governing grants administration and management will apply. Although this program is provided for in the financial plans of the NIAID, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Funding beyond the first and subsequent years of the grant will be contingent upon satisfactory progress during the preceding years and availability of funds. At this time, the NIAID has not determined whether or how this solicitation will be continued beyond the present RFA. RESEARCH OBJECTIVES Applications in response to this RFA must be prepared using a modified (abbreviated) grant application format; specific instructions for completing the application are in the special brochure (see INQUIRIES below). Background Immunosuppressive agents and therapeutic approaches developed in the last decade have significantly improved short-term graft survival. However, long-term graft survival remains poor, with 50 to 90 percent percent of all grafts failing within five years depending on what organ is transplanted. An improved understanding of the factors responsible for chronic rejection is critical to advancing effective therapeutic regimens. Among the gaps in our current knowledge are: factors determining the onset and severity; targets of immune reactivity; and control or regulation of the process of chronic rejection. These gaps have hindered the development of effective and safe treatments. Overcoming chronic rejection is important to increasing graft and patient survival and quality of life for transplant recipients and reducing the need for retransplantation which directly affects the supply of donor organs. Therefore, overcoming chronic rejection will consequently reduce health care costs. Research Objectives and Scope The research objective of this RFA is to support basic and clinical research on the immunopathogenesis of chronic solid organ graft rejection which will, in turn, lead to improved methods of diagnosis and treatment. The fact that chronic rejection exists in the face of the aggressive immunosuppression routinely administered to every transplant recipient illustrates the ineffectiveness of current therapeutic approaches. The recent literature on chronic rejection is primarily descriptive and our understanding of chronic rejection remains poor in several areas, including: the basic immunobiology of chronic rejection; diagnostic criteria and timing of diagnostic tests; and methods to prevent or reverse this process. Among the unresolved issues are: what are the cell types (TH1 vs. TH2) responsible for chronic rejection; what cytokines do they elaborate and what is their specificity; what can explain the presence of graft infiltrating T cells in transplanted organs without chronic rejection; what role, if any, do antibodies play in chronic rejection and what is the contribution of antibody-dependant-cell-cytotoxicity (ADCC) to chronic rejection? Criteria for the diagnosis of chronic rejection also need clarification. At present, diagnosis is made on the basis of loss of organ function combined with tissue biopsy. Ideally, it would be preferable to develop the knowledge and capability to diagnose chronic rejection prior to the loss of organ function. Further delineation of the immune parameters that are diagnostic of the onset of chronic rejection are needed to allow earlier diagnosis and intervention. Similarly, the successful reversal of ongoing chronic rejection will rely on understanding the basic processes of chronic rejection and may require new therapeutic agents or regimens. Applications should emphasize: collaborative research between basic scientists and clinical investigators; the use of new and innovative approaches to enhance understanding of the immunopathogenesis of chronic rejection and the clinical application and relevance of such approaches; and the use of the most up-to-date concepts and techniques of immunology. The inclusion of basic research and preclinical studies using laboratory animals is encouraged. However, animal models must be applicable to the treatment and/or prevention of human chronic graft rejection and the studies proposed must be directly relevant to understanding the underlying basic mechanisms of chronic rejection. Examples of studies relevant to this RFA include, but are not limited to, the following: o Identification of the targets of the immune response in chronic rejection. Are the antigens being recognized by the effector cells of chronic rejection identical to those being recognized in acute rejection? If not, what are the differences and how are they recognized? What are the relative contributions of T and B cells to the process of chronic rejection? o Further delineation of the molecular process of chronic rejection, including studies on cytokines or infiltrating cell types, initiating as well as mediators, and methods to attenuate the actions of these cells. o Development of new and innovative therapeutic approaches for the treatment and/or prevention of chronic rejection. o Development of new and innovative approaches or improvement of existing approaches to the earlier detection of chronic rejection. For example, would routine biopsies at regular intervals enhance predictive capability? What approaches could distinguish between clinically relevant pathologic changes (e.g., interstitial inflammation, fibrosis, vascular intimal hyperplasia) associated with acute vs. chronic rejection? What are the important components and the potential effectiveness of using a standardized, post-transplant assessment approach for the earlier detection of chronic rejection? 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 sub-populations 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 28, 1994 (FR 59 14508-14513) and printed 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 July 1, 1995, a letter of intent that includes a descriptive title of the overall proposed research, the name, address, and telephone number of the Principal Investigator, a list of the key investigators and their institution(s), and the number and title of this RFA. Although the letter of intent is not required, is not binding, does not commit the sender to submit an application, and does not enter into the review of subsequent applications, the information that it contains allows NIAID 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. Justina Schwemberger at the address listed under INQUIRIES. APPLICATION PROCEDURES NOTE: SEE BROCHURE FOR SPECIAL INSTRUCTIONS FOR COMPLETION OF GRANT APPLICATIONS IN RESPONSE TO THIS RFA. Applications are to be submitted on form PHS 398 (rev. 9/91), the standard application form for research grants. Application kits 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 301/710-0267. Applicants must adhere to the format and requirements specified in the PHS 398 application kit. 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. For purposes of identification and processing, mark "YES" in item 2a on the face page of the application and type in the RFA number, AI-95-009, and the title "IMMUNOPATHOGENESIS OF CHRONIC GRAFT REJECTION." The RFA label available in the form PHS 398 must be affixed to the bottom of the face page of the original 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. The signed, typewritten original of the application, including the Checklist, and three exact single-sided copies must be sent to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies and all five sets of appendices must also be sent to Dr. Justina Schwemberger at the address listed under INQUIRIES. To ensure their review, applications must be received by both the Division of Research Grants and Dr. Justina Schwemberger by October 17, 1995. Applications not received by October 17, 1995 will be considered non-responsive and will be returned to the applicant without review. Concurrent submission of an R01 and a Component Project of a Multi-project Application: Current NIH policy permits a component research project of a multi-project grant application to be concurrently submitted as a traditional individual research project (R01) application. If, following review, both the multi-project application and the R01 application are found to be in the fundable range, the investigator must relinquish the R01 and will not have the option to withdraw from the multi-project grant. This is an NIH policy intended to preserve the scientific integrity of a multi-project grant, which may be seriously compromised if a strong component project(s) is removed from the program. Investigators wishing to participate in a multi-project grant must be aware of this policy before making a commitment to the Principal Investigator and awarding institution. Special Instructions for Completion of Applications in Response to This RFA The NIH has recently been designated a "reinvention laboratory" by the Public Health Service. One NIH reinvention objective is to simplify and improve each stage in the grant process: application, review, award, and administration Experiments are being conducted to determine how to reduce the administrative burden in applying for an NIH grant without compromising the information needed by the initial scientific peer review group to assess the scientific merit of the application and the reasonableness of the proposed budget. The brochure, Instructions for Abbreviated Applications for Program Project (P01) Grants in Response to RFA-AI-95-009, Immunopathogenesis of Chronic Graft Rejection, presents specific instructions for sections of the PHS 398 (rev. 9/91) application form, which should be completed differently than usual. Some sections in the application are modified and others should not be completed for submission of the application, but will be requested if the application receives a score in the fundable range. For all other items in the application, follow the usual instructions on pages 9-32 of the PHS 398 booklet. REVIEW CONSIDERATIONS Review Procedures Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants (DRG) and for responsiveness by NIAID 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 NIAID 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 and the official signing for the applicant organization will be notified. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council. Review Criteria The review criteria for P01 grant applications in response to this RFA are presented in the special brochure. The program project grant application should include a justification for the appropriateness of that granting mechanism for the proposed project. The distinguishing features of a program project grant include: o A well-defined, unifying goal or problem area of research to which each project relates and contributes, thereby producing a research environment that allows each research effort to share the creative strengths of others. o A program director who possesses recognized scientific and administrative competence. He/she must demonstrate a substantial commitment to the program in time and effort thereby exercising leadership in providing overall direction and in upholding rigorous scientific conduct. o Each research project must, as assessed by peer review, stand on its own independent scientific merit, as well as complement other projects whenever feasible. o The projects require the participation of established investigators in several disciplines or investigators with special expertise in several areas of one discipline. All investigators must contribute to and share the responsibilities of fulfilling the program objective. o Ability of the proposed research to provide both basic immunological knowledge and clinically relevant interventions that will result in improvement in the methods to control solid organ chronic rejection. The appropriateness of the proposed experimental plan to validate the utility of the chosen strategy will be considered in this regard. AWARD CRITERIA Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program priorities, 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. Requests for the brochure "Instructions for Abbreviated Applications for Program Project (P01) Grants in Response to RFA AI-95-009, Immunopathogenesis of Chronic Graft Rejection," as well as inquiries regarding programmatic issues, may be directed to: Stephen M. Rose, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Solar Building, Room 4A14 6003 Executive Boulevard Bethesda, MD 20892-7640 Telephone: (301) 496-5598 FAX: (301) 402-2571 Email: sr8j@nih.gov Direct inquiries regarding review issues, address the letter of intent to, and mail two copies of the application and all five sets of appendices to: Justina S. Schwemberger, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C14 6003 Executive Boulevard Bethesda, MD 20892-7610 Telephone: (301) 496-9977 FAX: (301) 402-2638 Email: js74g@nih.gov Direct inquiries regarding fiscal matters to: Ms. Barbara Huffman Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C26 6003 Executive Boulevard Bethesda, MD 20892-7610 Telephone: (301) 496-7075 Email: bh23q@nih.gov Direct inquiries regarding the special instructions for preparation of the grant application to: John J. McGowan, Ph.D. Director, Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 3C20 6003 Executive Boulevard Bethesda, MD 20892-7610 Telephone: (301) 496-7291 FAX: (301) 402-0369 Email: ac20a@nih.gov Schedule Letter of Intent Receipt Date: July 1, 1995 Application Receipt Date: October 17, 1995 Scientific Review Date: February 1996 Advisory Council Date: May 1996 Earliest Date of Award: August 1996 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance, No. 93.855 - Immunology, Allergy, and Transplantation Research. Awards will be made under the authority 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 CRF 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 work place and promote the nonuse 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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