Full Text HD-97-004 MALE GERM CELL GROWTH AND DIFFERENTIATION NIH GUIDE, Volume 26, Number 14, May 2, 1997 RFA: HD-97-004 P.T. 34 Keywords: Embryology Human Reproduction/Fertility National Institute of Child Health and Human Development Letter of Intent Receipt Date: May 30, 1997 Application Receipt Date: June 13, 1997 PURPOSE The National Institute of Child Health and Human Development (NICHD) invites research project grant (R01) applications for the support of studies of male germ cell growth and differentiation. The establishment of effective culture systems for male germ cells is a prerequisite to obtaining a better understanding of the developmental mechanisms by which male germ cells develop into mature sperm cells. The lack of such culture systems has greatly hindered progress towards this understanding. One particular goal of this initiative is to improve our ability to culture the self-renewable spermatogonial stem cells in order to be able to conduct cause and effect experiments. It may also be possible to establish lines of these potentially immortal stem cells. These advances, coupled with a recent breakthrough in our ability to transplant these cells into the testes of infertile mice would establish a test system for the assessment of the developmental potential of the cultured and transplanted spermatogenic cells. This system also would provide the opportunity to study ways to genetically alter male germ cells such that these alterations can be passed on to the next generation through mature sperm and fertilization. It is expected that the new knowledge derived from these studies will lead to the alleviation of certain forms of male infertility and to the discovery of novel contraceptive approaches as well as to a wide array of other potential benefits. An important part of the mission of NICHD is to gain new knowledge about human reproduction and this Request for Applications (RFA) is designed to address that mission. 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, Male Germ Cell Growth and Differentiation, is related to the priority area of family planning. 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. Racial/ethnic minority individuals, women and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT The funding mechanism to be used to assist the scientific community in achieving the objectives of this RFA will be the National Institutes of Health (NIH) research project grant (R01). Responsibility for the planning, direction and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed five years. The earliest expected award date is December 1, 1997. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. New applications, as well as competing renewal applications for an ongoing research project, may be submitted in response to this RFA. FUNDS AVAILABLE Although this solicitation is included in the NICHD plans, support for these grants is contingent upon the availability of funds for this purpose. The number of grants to be awarded is also contingent upon a sufficient number of applications deemed meritorious enough to be considered for an award. It is anticipated that an estimated total cost of $540,000 will be available for the first year to support approximately three grants. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the size of the awards will also vary within the funding limits available. RESEARCH OBJECTIVES Background It is estimated that as many as 10% of reproductive age couples in the United States are infertile. Within this context, approximately 40% of human infertility cases are correlated with disorders in the male. We also recognize that there have been pills and other contraceptive methods available for female contraception for many years, but male contraceptive methods have been limited mostly to vasectomies and condoms. This should not be surprising since our knowledge of the process of spermatogenesis is negligible. New technologies and motivations now exist that could improve this knowledge. With this improved knowledge, it should be possible to greatly increase our ability to regulate male reproduction and to address these two issues of male infertility and male-side contraception, using new modes of diagnosis and therapy as well as providing additional contraceptive choices. Accordingly, the purpose of this RFA is to stimulate and encourage the development of culture systems for spermatogonial stem cells, the most immature, yet completely self-renewable, germ cells in the testis. These cells undergo growth, meiosis and differentiation in their development into mature sperm cells. However, the male and female gametes of mammals develop internally from spermatogonial and oogonial stem cells in the testis and ovary, respectively. Likewise, mammalian fertilization is internal and the various stages of embryonic development also occur internally so that it is difficult to observe these processes as they occur naturally. For egg development, as well as fertilization and early embryo development, culture systems have now been devised that allow one to observe and to conduct experiments and then to test the developmental potency of the oocyte or fertilized egg or early embryo by placing them back into the female reproductive tract for further development. These culture systems are still far from ideal, but they do permit considerable experimental manipulations to be done and cause and effect conclusions to be made. However, our ability to culture male germ cells is severely limited to brief and disconnected periods during the transition from spermatogonial stem cells to mature sperm. Thus, we have a very poor understanding of the mechanisms that control the development of spermatogonial stem cells into mature sperm. A recent breakthrough in male reproduction was the successful transplantation of spermatogonial stem cells from one testis to an infertile testis of the same or a different species and the ability to cryopreserve these spermatogonial stem cells prior to transplantation. The transplanted stem cells were able to undergo apparently normal spermatogenesis. This, then, established an in vivo system for assessment of the developmental potency of male germ cells after various in vivo or in vitro treatments, that might include production of cell lines with specific genetic alterations. With this technology, it will now be possible to test the in vivo developmental potential of stem cells that have developed in vitro. This opportunity to conduct rigorous in vivo tests of the developmental potential of male germ cells produced in this manner fills in one of the key voids in the technical armamentarium for male reproduction. This technology will be necessary in order to make rapid progress towards improved scientific understanding of male reproduction and towards practical applications that will have broad benefits to human health. Some of the benefits to human health that may be derived from increased knowledge of spermatogenesis through culture system improvements for spermatogonial stem cells include 1) major new insights into the genetic and other causes of certain types of male infertility that could lead to 2) development of effective points of alleviation of this infertility through assisted reproductive technologies, 3) discovery of novel contraceptive approaches, 4) the possibility that defective genes can be corrected in spermatogonial stem cell lines that can then be used therapeutically to eliminate certain devastating genetic diseases, 5) a vastly enhanced opportunity to understand how stem cells work in general since the spermatogonial stem cell population has the property of self-renewal, and 6) provide an additional method to generate transgenic animals as models of human diseases and disorders that may have certain advantages over the egg microinjection and the embryonic stem cell methods. There have been several recent NIH conferences and workshops and a detailed Institute of Medicine study that clarified the need for enhanced support of research in the area of this RFA. The conferences were 1) October 1991, "Meiosis II: Contemporary Approaches to the Study of Meiosis," 2) February 1992, "Opportunities in Contraception: Research and Development," 3) March 1993, "A New Look at Spermatogenesis," 4) August 1994, "Male Infertility and Impotence: Current Perspectives and New Directions for Basic and Clinical Research," 5) November 1994, "The Germ Line," and 6) May 1996, "Workshop on Transgenic Mouse Sperm Cryopreservation." The Institute of Medicine Report published in 1996 by the National Academy Press is on "Contraceptive Research and Development: Looking to the Future," and was based largely upon the "Workshop on Contraceptive Research and Development and the Frontiers of Contemporary Science," that was held in December, 1994 at the National Academy of Sciences. Much of the research reported and discussed at these meetings revealed a massive increase in molecular genetic approaches that could be applied to male reproduction. It was clear from these meetings that full advantage of this modern technology could not be currently applied to testicular germ cells owing to the unavailability of culture systems for these cells. Objectives The principal objective of this RFA is to stimulate and encourage the development of culture systems for spermatogonial stem cells. Our knowledge of the mechanisms by which spermatogonial stem cells develop into mature sperm is negligible. In order to fill this void in our knowledge it is imperative that we be able to conduct experimentation and make detailed observations of the various phases of spermatogenesis that include cell proliferation, meiosis and spermiogenesis. Meeting this principal objective is expected to help to improve our basic knowledge of sperm development and to rapidly advance our ability to apply this knowledge to key aspects of the mission of NICHD in alleviating infertility and in discovering novel contraceptive leads. In order to create a satisfactory culture system for this objective, it will be necessary to be able to obtain, identify and characterize high quality spermatogonial stem cells. These will be spermatogonia that are capable of self-renewal. Primary culture systems for these spermatogonial stem cells could be established that would allow for cell replication and observations and testing. The establishment of stable tissue culture lines of these spermatogonial stem cells would vastly facilitate reaching the objectives of this research, for these could then be used as a starting point for development of full in vitro or in vivo development of spermatogenic cells through the formation of mature sperm. The spermatogonial stem cell lines could be genetically altered, and then sperm could be used to carry altered genes into the next generation. While there has been considerable success in obtaining highly purified yields of these spermatogonial stem cells from mouse and rat testes, there is still much work to be done in identifying and characterizing them. The determination that they are of high quality can only be accomplished by showing that they have full developmental potential to develop into mature sperm that are capable of fertilizing an egg and resulting in healthy offspring. Currently, this latter aspect of the research can be done through transplantation of spermatogonial stem cells into infertile testes, where development has been shown to proceed through spermatogenesis and result in mature sperm. This procedure is presently inefficient, however, and improving the efficiency is a necessary part of the objectives of this RFA. It may be that a more favorable genetically or chemically-induced infertile testis model may be selected or developed that would provide better efficiency than those that have been used to date. Research Scope For this RFA, an application could focus upon, but would not be limited to, any of the following: o improvements in the isolation, identification, characterization and culture of spermatogonial stem cells of mammals o improvements in the ability to culture spermatogonial stem cells in such a way as to maintain their developmental potential o establishment of stable tissue culture lines of spermatogonial stem cells o improvements in the in vitro development of spermatogonial stem cells into mature sperm or advanced stages of spermatogenesis o improvements in the efficiency of transplantation of spermatogonial stem cells into seminiferous tubules Since this list is not meant to be all inclusive, prospective applicants are encouraged to discuss program relevancy issues with the program staff contact listed under INQUIRIES. In addition, be aware that awards made through this RFA would be restricted from supporting research on attempting to fertilize human eggs or on human eggs that (1) failed to fertilize, (2) are polyspermic, (3) are parthenogenetic, either by attempts to specifically activate or that were discarded after attempted IVF, or (4) are derived from fetal ovaries with the intent to attempt fertilization or artificial activation. Other research on human embryos that is not part of clinical protocols and/or general procedures in human IVF clinics as specifically authorized by prior approval of the NICHD is also restricted from support through an award from 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 is 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 in the NIH Guide for Grants and Contracts, Vol. 23, No. 11, March 18, 1994. LETTER OF INTENT Prospective applicants are asked to submit, by May 30, 1997, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains allows NICHD 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. Richard J. Tasca at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these awards. These forms are available at most institutional offices of sponsored research; and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892, telephone 301-710-0267, e-mail asknih@odrockm1.od.nih.gov. 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 title, MALE GERM CELL GROWTH AND DIFFERENTIATION, and number, RFA HD-97-004, must be typed on line 2a of the face page of the application form and the YES box must be checked. 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 to: Susan Streufert, Ph.D. Division of Scientific Review National Institute of Child Health and Human Development Building 61E, Room 5E03 Bethesda, MD 20892-7510 Bethesda, MD 20852 (for express/courier service) Telephone: (301) 496-1485 FAX: (301) 402-4104 Email: StreufeS@hd01.nichd.nih.gov Applications must be received by June 13, 1997. 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 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. The NICHD will not accept for review competing new or continuation applications that have been revised more than one time. If a revised competing continuation application is not selected for funding, the applicant institution may then only submit a new, substantially different application. Schedule Letter of Intent Receipt Date: May 30, 1997 Application Receipt Date: June 13, 1997 NACHHD Council Review: September 1997 Earliest Award Date: December 1, 1997 REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by DRG and responsiveness to the RFA by NICHD staff. Incomplete applications will be returned to the applicant without further consideration. Any application that does not meet the minimum requirements of this RFA will be considered unresponsive to the RFA and returned to the applicant. Applications meeting the minimum requirements and 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 usual NIH peer review procedures for research grants and the review criteria stated below. As part of the initial merit review, a process may be used in which applications will be determined to be competitive or noncompetitive based on their scientific merit relative to other applications received in response to this RFA. Applications determined to be noncompetitive by the review committee will be withdrawn from further consideration, and the principal investigator will receive a summary statement reflecting the reviewers' evaluation. Applications judged to be competitive will be further discussed and assigned a priority score. They will then receive a second level review by the National Advisory Child Health and Human Development Council (NACHHD). Review criteria for RFAs are generally the same as those for unsolicited research grant applications, including: o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach and methodology proposed to carry out the research; o qualifications and research experience of the Principal Investigator and staff, and of collaborators, if applicable; o adequacy of time and effort dedicated to the project; o availability of the resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research; o 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. (See INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS); o appropriateness of policies to ensure the protection of human subjects and the humane care and use of laboratory animals. AWARD CRITERIA The anticipated date of award is December 1, 1997. Applications approved by the NACHHD Council will be considered for award based upon scientific and technical merit, program balance, and 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 scientific program issues and address the letter of intent to: Richard J. Tasca, Ph.D. Reproductive Sciences Branch National Institute of Child Health and Human Development Building 61E, Room 8B01 Bethesda, MD 20892-7510 Telephone: (301) 496-6515 FAX: (301) 496-0962 Email: tascar@hd01.nichd.nih.gov Direct inquiries regarding fiscal matters to: Ms. Melinda Nelson Office of Grants and Contracts National Institute of Child Health and Human Development Building 61E, Room 8A17 Bethesda, MD 20892-7510 Telephone: (301) 496-5481 FAX: (301) 402-0915 Email: nelsonm@hd01.nichd.nih.gov AUTHORITY AND REGULATIONS This Program is described in the Catalog of Federal Domestic Assistance Number 93.864, Population Research. Awards are 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). These special Terms of Award are in addition to, and not in lieu of, otherwise applicable OMB administrative guidelines administered under PHS grants policies and Federal Regulations 45 CFR 52 and 45 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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