Full Text HD-97-002 ONTOGENY OF PERINATAL HOST DEFENSES NIH GUIDE, Volume 26, Number 11, April 4, 1997 RFA: HD-97-002 P.T. 34 Keywords: 0775013 Infants Immunology Biology, Cellular Biology, Molecular National Institute of Child Health and Human Development Application Receipt Date: June 10, 1997 PURPOSE The National Institute of Child Health and Human Development (NICHD) of the National Institutes of Health (NIH) invites innovative and hypothesis-driven basic research project grant (R01 and R29) applications designed to study the ontogeny of immunity and host defense mechanisms in the fetus, neonate and infant. The primary objectives are to promote research to study the: 1) cellular, molecular and genetic elements and mechanisms responsible for the ontogeny of host defenses; 2) developmental biology of host defense mechanisms in response to perinatal and postnatal infections; 3) key cells, cytokines, cytokine-receptors, their interactions, and signal transduction events involved in perinatal and postnatal host defense; 4) role, function, mechanisms and interactions of maternal transplacental and colostral transfer of specific immunity on the development and responsiveness of perinatal host defenses; and 5) abnormal host defenses in early development that result in infant morbidity and/or mortality. Of particular interest are applications studying the development of basic perinatal host defense mechanisms in humans and non-human primates. 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), Ontogeny of Perinatal Host Defenses, is related to the priority areas of maternal and infant health, and immunization and infectious diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-512-1800). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Foreign institutions are not eligible for the First Independent Research Support and Transition (FIRST) (R29) award. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Competing continuation applications for already funded projects will NOT be eligible for awards from NICHD under this RFA. MECHANISM OF SUPPORT The mechanisms of support will be the individual research project grant (R01) and FIRST (R29) awards. Applications for FIRST Awards and R01s from new investigators are particularly encouraged. The total project period for R29 applications is five years. R01 applications submitted in response to this RFA may not exceed four years; foreign applications may not request more than three years of support. The applicant will be responsible for planning, directing and executing the proposed project. The anticipated award date is September 30, 1997. This RFA is a one-time solicitation. Future competing renewal applications will compete with all unsolicited investigator-initiated applications and will be reviewed according to standard NIH peer review procedures. FUNDS AVAILABLE The estimated funds available for the total (direct and facilities and administrative) first-year costs of all awards made under this RFA will be $1,500,000. It is anticipated that the NICHD will award up to eight R01/R29 grants for fiscal year 1997. The awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. The usual PHS policies governing grants administration and management, including facilities and administrative (F & A) costs, will apply. Although this initiative is provided for in the financial plans of the NICHD, 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 The Center for Research for Mothers and Children (CRMC) of the NICHD supports basic, translational and clinical research on maternal/child health; pregnancy and parturition; normal and abnormal embryonic, fetal and perinatal development; reproductive and developmental immunology; congenital, perinatal and postnatal infections; Sudden Infant Death Syndrome (SIDS); and therapeutic and prevention strategies to reduce infant morbidity and mortality. The Developmental Biology, Genetics and Teratology Branch, and Pregnancy and Perinatology Branch of the CRMC are particularly interested in supporting basic studies on the ontogeny of perinatal host defenses and developmental and reproductive immunobiology. The goal of these basic studies is to provide important fundamental knowledge, understanding and insights that will translate into safe and efficacious perinatal prophylactic and therapeutic modalities, as well as useful prevention strategies to reduce infant morbidity and mortality. Host defense mechanisms that protect the fetus, neonate and infant are varied, complex and interactive. Host genetic and environmental factors appear to play an important role in the development of host defenses. Non-specific, natural or innate host defense mechanisms include physical and chemical barriers; humoral components (e.g., serum opsonins, complement factors, fibronectin, c-reactive proteins, and lactoferrin); natural killer (NK) cells; phagocytic cells (e.g., neutrophils, monocytes, macrophages); as well as soluble plasma and tissue proteins that amplify the action of phagocytes to become natural immune effector cells. Specific, adaptive or acquired host defense mechanisms are comprised primarily of cell-mediated (T lymphocyte) and humoral (B lymphocyte and immunoglobulin) systems. Both non-specific and specific immune mechanisms are essential for immunocompetence of the host. Moreover, they are interdependent and intimately related. For example, monocytes and macrophages are important components of both non-specific and specific immune defense mechanisms. Macrophages act not only as important effector cells in the expression of non-specific immunity; they also act as antigen-processing and presenting cells that play a critical role in triggering specific immunity mediated by B and T lymphocytes. In recent years, our knowledge and understanding of human adult and rodent immunology and host defense mechanisms have advanced rapidly and significantly. This has been made possible by the rapid and revolutionary advances in biochemical, cellular, molecular, genetic and transgenic technologies. Nevertheless, large gaps in basic developmental immunobiology and the molecular mechanisms of host defenses in perinatal and postnatal humans and primates still remain and need to be addressed. These gaps cannot always be extrapolated from adult human or rodent studies. For example, although the immune system of the full-term human fetus is almost functionally mature, in general it is not as efficient as the adult immune system. There are definite functional differences between the adult and neonatal immune systems. At birth the neonatal B and T lymphocytes are generally naive and unprimed, so they have not undergone antigen-induced clonal expansion or maturation. This partially accounts for the human neonate's susceptibility to infection. Although neonatal B lymphocytes are mature and functional, they are unable to produce some specialized antibodies such as IgA and IgG2 against some types of encapsulated bacteria. The neonatal T lymphocyte repertoire is somewhat functionally immature compared to adult T lymphocytes. Important functional differences in neonatal T lymphocytes include diminished capacity to provide help for or actual suppression of immunoglobulin production by B lymphocytes, diminished generation and activity of cytotoxic T lymphocytes, and decreased capacity to activate macrophages. Neonatal T lymphocytes also have a markedly diminished capacity to produce certain cytokines (e.g., IFN-gamma and IL-4). Recent studies indicate that antigenic naivete is the principal mechanism for selective lymphokine deficiency in neonates. It is clear that additional studies targeted to perinatal humans and primates, as well as relevant animal models, need to be conducted to fully elucidate and understand the ontogeny and mechanisms of perinatal host defenses. Other areas which require additional research are the role, mechanisms and interactions of maternal immunity in perinatal host immune defenses. This is especially important in humans and primates, where the molecular mechanisms and impact of perinatal transplacental and colostral transfer of specific immunity need better understanding. Clearly, a better knowledge and understanding of perinatal host defenses and maternal immune interactions have important clinical implications. Perinatal host defenses are not identical to adult host defenses. Fetuses and neonates are generally less capable of coping with perinatal infections. For example, primary HIV-1, herpes virus, and toxoplasma infections in a fetus are usually more severe and aggressive than in an adult. Thus, some of the parameters and criteria for diagnosing, staging and treating perinatal infections are different compared to an adult. A knowledge of the temporal development of immunity and perinatal host defense mechanisms is thus clinically important for treatment of congenital and perinatal infections. Understanding the sequential development of host immune defenses is also crucial for developing and administering vaccines. The timing for immunization should be based on a thorough and rational understanding of the ontogeny and sequential development of immunity. This would maximize the specificity, level and duration of immunologic protection. In recent years, modern advances in neonatal intensive care units have increased the survivability of premature and low birth weight babies. This new group of babies is generally not sufficiently developed to cope with the extrauterine environment without assistance. Their immaturity predisposes them to a multitude of problems, including pulmonary viral infections. Moreover, their underdeveloped immune system and host defenses severely compromise their ability to produce antibodies and mount a protective and specific host immune response. These preterm babies also tend to have lower maternal IgG levels compared to term babies. This leaves them vulnerable to the detrimental effects of many infectious agents. In these premature babies, it is essential to find effective means of enhancing or accelerating the development of their host immune defenses. This requires a basic understanding of how and when the components of the immune system and host defenses develop as well as the key cellular, molecular and genetic elements and mechanisms that drive their sequential development. Finally, the relationship of SIDS to the developing immune system and host defense response to infection needs further exploration. Several studies suggest that mild respiratory or gastrointestinal tract infections are predisposing factors in infants who succumb to SIDS. A few studies implicate toxigenic bacteria as etiologic agents. Other reports suggest that abnormal immune responses such as hypersecretion of immunoglobulins in the respiratory tract, elevated interleukins, or anaphylaxis play a role in SIDS pathogenesis. Thus it is important to understand how abnormal or delayed development of host immune defenses contribute to SIDS. The recent advances in molecular biology and genetics provide new opportunities, insights and technologies for studying the development of the immune system and perinatal host defense mechanisms. The temporal expression of important developmental genes and the actions and interactions of their gene products (e.g. cytokines) can now be studied. This makes it feasible to molecularly and biologically dissect and characterize the key elements, mechanisms and signal transduction pathways that are important in the ontogeny of host immune defense mechanisms. It also provides critical information for developing new approaches and biotechnologic and pharmaceutic products either for enhancing positive or blocking adverse host defense mechanisms in vivo. This RFA was developed primarily to address the large gaps in our basic knowledge and understanding of the developing immune system and perinatal host defenses in humans and primates. It was also stimulated by the 1996 Report of the NIH AIDS Research Program Evaluation Working Group. Although the report focused on AIDS, it also addressed the critical need for high-quality, novel or innovative, investigator-initiated, basic research studies to better understand the human and primate immune systems. Furthermore, it strongly encouraged increasing research support for selected understudied and underfunded areas of basic human immunobiology and physiology, and the development of host defense mechanisms against infection in the neonate. New knowledge in these areas would greatly benefit our understanding of pediatric AIDS and translate into effective prophylactic, therapeutic and prevention strategies. The work group described important gaps in our basic knowledge of the immune system, but it also revealed promising new opportunities, insights and approaches for future research. Research Scope The objective of this RFA is to encourage and promote innovative and hypothesis-driven basic research projects, primarily in humans and primates, but also in relevant animal models, to study the ontogeny of specific or acquired perinatal host defense mechanisms; the sequential acquisition of antigen-specific perinatal cell-mediated and antibody-mediated immune responses; and the major differences between perinatal and adult immunity and host defenses. This RFA is for applications focused primarily on the ontogeny and host defense mechanisms of perinatal and postnatal T lymphocytes, B lymphocytes, immunoglobulins, monocytes, macrophages, NK cells and their associated specific humoral components. Studies which address the role and mechanisms of transplacentally and colostrally acquired specific humoral and cellular elements on perinatal host defense are appropriate for this RFA. Studies on perinatal neutrophils, natural humoral factors (such as opsonins, complement, fibronectin, C-reactive protein and lactoferrin) and non-specific substances in breast milk are beyond the scope of this RFA. Applications on these latter topics will be considered non-responsive and returned to the applicant. The research scope includes basic studies listed in the PURPOSE section of this RFA. The following are examples of research topics that are appropriate for this RFA; however, they are not to be considered as exclusive or limiting: o Identify and characterize genes encoding specific proteins essential for the ontogeny of immunity and host defenses. o Elucidate the biochemical, cellular, molecular and genetic elements and mechanisms responsible for the development of host defenses during perinatal infections. o Identify specific cytokines, their receptors and transcription factors, and define their role in development of perinatal host defense mechanisms. o Identify and characterize the genes and their protein products involved in cytokine-receptor signaling pathways; elucidate the molecular mechanisms of signal transduction and pathways that are important for development and responsiveness of host defenses. o Identify MHC genes and their products that are important in the ontogeny of perinatal host defenses; determine the mechanisms of class I and class II HLA antigens in the induction and expression of perinatal cellular and humoral immunity. o Elucidate how specific congenital or perinatal infections may impair or delay the development of perinatal host defenses. o Determine how inherited and acquired immunodeficiencies may compromise the ontogeny of perinatal host immune defenses. o Elucidate the molecular mechanisms involved in transplacental and colostral transfer of specific immunity to the fetus and neonate. o Study the host genetic and environmental factors which affect the ontogeny of host defenses. o Characterize the molecular and cellular basis of immune recognition of perinatal infectious agents; determine the role and ontogeny of specific host defenses; and define the molecular basis for perinatal T cell receptor diversity and immunogenetic regulation of specific T cell responses. o Develop primate and other animal models that will be useful for understanding the basic development of perinatal host defenses and responsiveness to infection. o Develop and use appropriate transgenic mouse models to identify and elucidate important molecular genetic mechanisms responsible for ontogeny of perinatal host defenses. o Determine the role of host immune responses in the pathogenesis of SIDS. The areas of interest listed above are not in any order of priority. They are only suggested examples of areas of research to consider. Applicants are encouraged to propose other areas that are related to the objectives and scope of this RFA. 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 are provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This 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 the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 5/95). Applications kits are available at most institutional 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: ASKNIH@odrockm1.od.nih.gov; and from the NICHD program administrator listed under INQUIRIES. Since a letter of intent is not solicited or required, applicants are strongly encouraged to contact NICHD program staff listed under INQUIRIES in the early stages of preparing the application. For all applications, the RFA label available in the PHS 398 (rev. 5/95) 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, the RFA number, HD-97-002, and the RFA title, ONTOGENY OF PERINATAL HOST DEFENSES, must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit 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 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 also be sent or delivered under separate cover to: Susan Streufert, Ph.D. Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03 - MSC-7510 Bethesda, MD 20892-7510 Rockville, MD 20852-7510 (for express/courier service) Telephone: (301) 496-1485 FAX: (301) 402-4104 Email: StreufeS@HD01.nichd.nih.gov Applications prepared in response to this RFA must be received by June 10, 1997. If an application is received after that date, it will be returned to the applicant 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. The DRG will not accept any application that is the same as one already reviewed. This does not preclude submission of a substantially revised application already reviewed, but such an application must include an introduction addressing the previous critique. FIRST (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. 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. Applications for the FIRST (R29) award must comply with the NIH Guidelines for FIRST awards and the Just-in-Time procedures announced in the NIH Guide, Vol. 25, No. 10, March 29, 1996. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and responsiveness by the NICHD. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, DRG staff may contact the applicant to determine whether to return the application to the applicant or submit it for review in competition with unsolicited applications at the next review cycle. 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 NICHD in accordance with the review criteria stated below. As part of the initial merit review, a process 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, assigned a priority score, and receive a second level of review by the National Advisory Child Health and Human Development (NACHHD) Council. 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. A summary statement will be prepared for non-competitive applications. Review Criteria Review criteria for this RFA are generally the same as those for unsolicited NIH research project grant applications. o scientific, technical, or medical significance and originality of proposed research; o appropriateness, feasibility and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications, competence and research experience of the Principal Investigator and staff, particularly, but not exclusively, in the area of the proposed research; o availability of the resources and facilities necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o for research involving human subjects, adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. The initial review group will also examine the provisions for the protection of human and animal subjects, and the safety of the research environment. Furthermore, it will consider and evaluate how the proposed research would advance the goals targeted in this RFA. AWARD CRITERIA The anticipated date of award is September 30, 1997. Applications recommended by the NACHHD Council will be considered for awards. Awards will be based on the scientific merit of the proposed project as determined by peer review, program priorities and balance of research areas targeted in the RFA, and availability of funds. INQUIRIES Written, telephone and email inquiries concerning this RFA are strongly encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct programmatic inquiries to: Allan Lock, D.V.M. Center for Research for Mothers and Children National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 4B01 - MSC-7510 Bethesda, MD 20892-7510 Telephone: (301) 496-5541 FAX: (301) 402-4083 Email: LockA@hd01.nichd.nih.gov Direct fiscal inquiries to: Mr. E. Douglas Shawver Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17 - MSC-7510 Bethesda, MD 20892-7510 Telephone: (301) 496-1303 FAX: (301) 402-0915 Email: ShawverD@hd01.nichd.nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.865 - Research for Mothers and Children. Awards are made under 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 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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