Full Text AI-94-023 THE MECHANISMS OF EMBRYONIC/FETAL-MATERNAL TOLERANCE NIH GUIDE, Volume 23, Number 24, June 24, 1994 RFA: AI-94-023 P.T. 34 Keywords: 0705048 Human Reproduction/Fertility Pregnancy Immunogenetics National Institute of Allergy and Infectious Diseases National Institute of Child Health and Human Development Office of Research on Women's Health Letter of Intent Receipt Date: August 15, 1994 Application Receipt Date: November 16, 1994 PURPOSE The Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases (NIAID); the Developmental Biology, Genetics, and Teratology Branch, the Center for Research for Mothers and Children, and the Reproductive Sciences Branch, Center for Population Research of the National Institute of Child Health and Human Development (NICHD); and the Office of Research on Women's Health (ORWH) of the Office of the NIH Director invite applications for basic studies designed to identify the underlying immunologic and/or genetic mechanism(s) that protect the embryo and fetus from maternal rejection and to elucidate the interactions of the fetal and maternal immune systems in successful pregnancy. Despite genetic differences known to elicit strong immunologic responses under other circumstances, i.e., Major Histocompatibility Complex (MHC) disparities, mothers do not reject their semiallogeneic embryos or fetuses. This remarkable immunologic accommodation is undoubtedly due to many finely orchestrated events. The goal of this initiative is to promote research that will advance our understanding of the underlying mechanisms of this unique form of immunologic tolerance and lead to improved clinical applications. 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), The Mechanisms of Embryonic/Fetal-Maternal Tolerance, is related to the priority areas of immunization and infectious diseases, family planning, and maternal and infant health. 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 institutions, such as universities, colleges, hospitals, laboratories, units of State or local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible to apply for First Independent Research Support and Transition (FIRST) (R29) Awards. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT The mechanisms of support will be the individual research project grant (R01) and the FIRST (R29) award. Multidisciplinary approaches that involve collaborative efforts among investigators in the fields of basic immunology, molecular biology, cell biology, biochemistry, and genetics are strongly encouraged. The total project period for an application submitted in response to this RFA may not exceed five years; a foreign application may not request more than three years of support. This RFA is a one-time solicitation. Future competing renewal applications will compete with all investigator-initiated applications and will be managed according to customary referral and review procedures. FUNDS AVAILABLE The estimated funds available for the total (direct and indirect) first-year costs of all awards made under this RFA will be $2,000,000. In Fiscal Year 1995, the NIAID and the ORWH plan to provide up to $1,000,000 to fund up to five R01 and/or R29s and the NICHD plans to provide up to $1,000,000 to fund up to six R01s and/or R29s. PHS policies governing grants administration and management will apply. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIAID, the NICHD, and the ORWH, 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. RESEARCH OBJECTIVES Background Pregnancy, which is experienced by over six million women per year in the United States, is an outstanding example of immune accommodation to immunologically incompatible tissue (embryonic/fetal). The operative mechanisms that permit the embryo and/or fetus to develop without being rejected, if identified, could provide insights into the induction, maintenance, and control of immunologic tolerance. Evidence suggests that protection of the embryo or fetus from maternal immunological rejection is multifactorial, possibly involving modulated or unique MHC/HLA expression, hormonal changes during pregnancy, unique expression of non-MHC cell surface molecules, and the specific function of cells and cytokines at the uteroplacental interface. For example, recent studies of the expression of the unique, nonpolymorphic HLA-G class I MHC molecule expressed primarily on extravillous trophoblast cells strongly implicate a role for the HLA system in fetal tolerance. Differential expression and/or repression of classical HLA class I molecules on embryonic or fetal tissue seems required for the maintenance of pregnancy and the regulatory molecular mechanisms are now being studied. Other cell surface molecules, such as complement regulatory proteins, may also be critical for embryonic and/or fetal survival. Although cells at the uteroplacental interface have been identified, the interactions of these cells, their products (cytokines) and receptors, and the roles they play in the protection of the embryo and fetus from maternal rejection remain incompletely described. Recent studies suggest unique control mechanisms exist that may, in part, ensure a tolerant environment, e.g., placental macrophages were found to have altered antigen processing function. Much interest has focussed on cytokines identified as important in establishing, maintaining, and regulating pregnancy, i.e., TGF-beta, TNF, IL-6, LIF, CSF-1, GM-CSF and IFN-gamma. Elucidating their regulation, expression in nonlymphoid tissue, and receptor biology, as well as the identification of other relevant receptor-ligand (cytokine) interactions that contribute to embryonic and fetal tolerance, is essential for a comprehensive understanding of this event. Understanding the basic mechanisms of embryonic/fetal-maternal tolerance has considerable potential for clinical application, e.g., controlling the transmission of infectious maternal disease to the fetus, devising and improving therapies for infertility, and identifying and preventing dysregulations that result in unsuccessful pregnancy. Research Objectives and Scope The objective of this RFA is to support innovative research designed to apply current research technologies and scientific advances to facilitate the identification of mechanisms that protect the embryo and fetus from maternal immunologic rejection as well as the elucidation of embryonic/fetal-maternal immune interactions. Suitable models of study may include in vitro and in vivo animal models, transgenic animal models, and human studies (preclinical or clinical). Relevant topics of research include, but are not limited to, the following: o The role of MHC in embryonic/fetal-maternal tolerance, including: - identification of regulatory mechanisms (transcription, translation and post-translational modifications) of MHC genes and functional expression, lack of expression, or repression on embryonic/fetal tissues as they relate to immune function; - differential MHC expression and the kinetics of this expression; and - identification of unique MHC molecule(s) involved in embryonic/fetal accommodation and elucidation of the mechanisms of this accommodation. o Studies of the expression and function of unique cell surface molecules (non-MHC molecules) that may play a role in embryonic/fetal protection. o The gene regulation and differential expression of cytokines and their receptors (soluble or membrane-bound) and the role this expression has on embryonic/fetal tolerance and successful pregnancy. o The role of immune cells in embryonic/fetal maternal tolerance, including: - identification of immune cell populations that have a regulatory role in embryonic/fetal tolerance and characterization of their effector function(s); and - delineation of the function(s) of immune cells found in the pregnant uterus and/or placenta which ensures a tolerant environment, e.g., altered antigen-processing/presentation ability of antigen presenting cells. o Interaction of the endocrine and immune system as it pertains to the induction and maintenance of embryonic/fetal-maternal tolerance. NOTE: Studies may address any post-fertilization influencing immunologic events. Studies of infectious disease as it relates to the regulation - or dysregulation - of embryonic/fetal- maternal tolerance are within the scope of this RFA with the exception of sexually transmitted diseases (STDs) and the Human Immunodeficiency Virus (HIV). In addition, development of treatments for infertility or miscarriages; and contraception development are not within the scope of this RFA. 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 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 has 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 August 15, 1994, a letter of intent that includes a descriptive title of the overall proposed research, the name, address and telephone number of the Principal Investigator, 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 NIH 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. Allan Lock at the address listed under INQUIRIES. APPLICATION PROCEDURES Applications are to be submitted on the research grant application form PHS 398 (rev. 09/91). For purposes of identification and processing, item 2a on the face page of the application must be marked "YES" and the RFA number and the words "THE MECHANISMS OF EMBRYONIC/FETAL-MATERNAL TOLERANCE" must be typed in. These application forms may be obtained from the institution's office for sponsored research or its equivalent and from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 5333 Westbard Avenue, Room 449, Bethesda, Maryland 20892, telephone (301) 710-0267. It is highly recommended that the appropriate NIAID or NICHD program contact be consulted before submitting the letter of intent and during the early stages of preparation of the application. (See program contacts in INQUIRIES below.) Applications must be received by November 16, 1994. Applications that do not conform to the instructions contained in PHS 398 (rev. 09/91) application kit, will be judged nonresponsive and will be returned to the applicant. The RFA label available in the application form PHS 398 must be affixed to the bottom of the face page. 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. FIRST award (R29) 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. Applications received after the receipt date will be returned without review. The Division of Research Grants (DRG) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. This does not exclude the submission of substantial revisions of an application already reviewed. These applications must, however, include an introduction addressing the previous critique. Submit a signed, typewritten original of the application, including the checklist, and three signed, exact, single-sided photocopies, in one package to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional exact copies of the grant application and all five sets of the appendix must also be sent to Dr. Olivia Preble at the address listed under INQUIRIES. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the NIH Division of Research Grants (DRG) and for responsiveness by NIAID and NICHD staff. Incomplete applications will be returned to the applicant without further consideration. If NIAID or NICHD staff find that the application is not responsive to the RFA, it will be returned 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 and the NICHD 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 promptly notified. The second level of review will be provided by the National Advisory Allergy and Infectious Diseases Council and/or the National Advisory Child Health and Human Development Council. The factors to be considered in the evaluation of scientific merit of each application will be those used in the review of unsolicited 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 adequacy and suitability of the facilities; and the adherence to NIH guidelines concerning adequate representation of women and minorities in clinical research. While the following review factors do not usually influence the priority score, they are nonetheless carefully considered by the initial review group: the appropriateness of the requested budget to the work proposed; and the adequacy of protection of human subjects and/or animals in research. Any documented concerns expressed by the initial review group about any of these factors on a given application may influence the recommendation of the Advisory Council concerning funding of that application. 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. Direct inquiries regarding programmatic issues and address the letter of intent to: M. Michele Hogan, Ph.D. Division of Allergy, Immunology and Transplantation National Institute of Allergy and Infectious Diseases Solar Building, Room 4A21 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7551 FAX: (301) 402-2571 Allan Lock, D.V.M. Center for Research for Mothers and Children National Institute of Child Health and Human Development Building 61E, Room 4B01 6100 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-5541 FAX: (301) 402-4083 Direct inquiries regarding review issues and mail two copies of the application and all five sets of appendices to: Olivia T. Preble, Ph.D. Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4C20 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-8208 FAX: (301) 402-2638 Direct inquiries regarding fiscal matters to: Ms. Cynthia R. McDermott Division of Extramural Activities National Institute of Allergy and Infectious Diseases Solar Building, Room 4B22 6003 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-7075 Mr. E. Douglas Shawver Office of Grants and Contracts National Institute of Child Health and Human Development Building 61E, Room 8A17K 6100 Executive Boulevard Bethesda, MD 20892 Telephone: (301) 496-1303 Schedule Letter of Intent Receipt Date: August 15, 1994 Application Receipt Date: November 16, 1994 Scientific Review Date: February 1995 Advisory Council Date: June 1995 Earliest Award Date: August 1995 AUTHORITY AND REGULATIONS The NIAID program is described in the Catalog of Federal Domestic Assistance, No. 93.855 - Immunology, Allergy and Transplantation Research; and the NICHD program in No. 93.864 - Population Research and No. 93.865 - Research for Mothers and Children. Awards for NIAID will be made under the authority of the Public Health Service Act, Title III, Section 301 (Public Law 78-410, as amended; 42 USC 241) and administered under PHS grants policies and Federal Regulations 45 CFR Part 74 and 92. Awards for NICHD are 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 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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