Full Text HD-95-018 MARKERS OF UTERINE RECEPTIVITY FOR BLASTOCYST IMPLANTATION NIH GUIDE, Volume 24, Number 33, September 22, 1995 RFA: HD-95-018 P.T. 34 Keywords: Human Reproduction/Fertility Pregnancy National Institute of Child Health and Human Development Letter of Intent Receipt Date: January 5, 1996 Application Receipt Date: February 8, 1996 PURPOSE The National Institute of Child Health and Human Development (NICHD) invites applications from investigators willing to participate in the ongoing multisite National Cooperative Program on Markers of Uterine Receptivity for Blastocyst Implantation with the NICHD through cooperative agreements. The primary goal of this Program is to improve the pregnancy rate in women who have difficulty in conceiving because of implantation failure. In order to achieve this goal, it is expected that investigators will identify markers indicative of the state of the uterus receptive for blastocyst implantation, characterize how these markers are involved in the process of blastocyst implantation, and develop noninvasive methods for measurement of markers. It is anticipated that the participating investigators will cooperate in interdisciplinary and complementary manners to achieve the goals of identification, characterization, and measurement of the receptivity markers. The ultimate beneficiaries of this Program would be people who have difficulty in attaining a pregnancy because of implantation failure, and others who may benefit from assisted reproductive and genetic methods. 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), National Cooperative Program on Markers of Uterine Receptivity for Blastocyst Implantation, 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 for-profit and non-profit organizations, public and private. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply. The need for continuous and active communications and interactions among sites dictates that only institutions in the continental United States will be eligible for participation. This recompetition is open to both new and competing continuation applications. MECHANISM OF SUPPORT Funding to assist the scientific community in undertaking this Program of basic and applied research will be through cooperative agreements (U01) between participating sites and NICHD. The major characteristic of a cooperative agreement is substantial scientific and/or programmatic involvement of the NIH staff Research Coordinator, above and beyond the levels required by the program management of grants. Specifically, an NICHD staff member will cooperate with the Principal Investigators as a partner in the research and serve as Research Coordinator. The Research Coordinator will assist the recipient(s) in a cooperative way, but without assuming direction, prime responsibility or a dominant role in the activity. In the cooperative agreement, which is an assistance mechanism and not an acquisition mechanism, the NIH purpose is to support, stimulate, and expedite the recipient's activities through a partnership role. All grantees in this Program will agree to accept the participatory and cooperative nature of the group process. Details of the responsibilities, relationships, and governance of the awards for this Program are discussed later in this document under Direction and Management: The Steering Committee and in Terms and Conditions of the Award. This RFA is a one-time solicitation for the purpose of the present competition. At this time, the NICHD has not determined whether or how this program will be continued beyond the present solicitation. Any future determination in this regard would be publicly announced. FUNDS AVAILABLE An estimated total of $1 million (including direct and indirect costs) will be available for the entire Program for the first year with an anticipated four percent increase for future years. It is anticipated that up to six awards (either new and/or competing continuation) will be made for a project period of four years with the start date of December 1, 1996. 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. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program 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. RESEARCH OBJECTIVES Background This cooperative program on Markers of Uterine Receptivity for Blastocyst Implantation was initiated on December 1, 1992 and the current award period will expire on November 30, 1996. Four sites have been participating in the current program, and the program will be opened for recompetition with anticipation of a greater number of participating sites and a wider range of research models including use of human tissues. The goal of this Cooperative Program is to identify useful markers that indicate the uterus is, or is going to be, in the receptive phase for blastocyst implantation and to examine how these markers, or factors, are involved in the process of blastocyst implantation. If it were possible to develop sensitive assays for such markers in blood, urine, saliva, tears, or perspiration, major clinical benefits would be feasible. Basic and applied research of this nature has significant implications for important problems in human infertility. Included among these problems are: 1. The uterus accepts a blastocyst for implantation for a limited period of time (the receptive phase) and then becomes refractory. Little is known about human markers that would distinguish the receptive phase from a refractory one. Such markers are urgently needed to facilitate treatment of the infertility caused by uterine refractoriness. 2. Hormonal treatments that induce ovarian follicle development in infertile patients perturb the normal sequence of events in the uterus. Little is known about what factors in the uterus are perturbed or how this affects the actual mechanism of blastocyst implantation. 3. There are three uterine conditions that indicate uterine receptivity, i.e., (1) the uterine condition that is receptive for blastocyst implantation in the fertile cycle and was prepared hormonally, without the presence of the preimplantation embryo; (2) the uterine condition that results from hormonal conditioning and the presence of the preimplantation (and implanting) embryo, and (3) the uterine condition that predictably procedes, by a certain amount of time, the forthcoming receptive phase. Although these conditions are theoretically distinguishable, it is not known whether or not these conditions may be distinguished. 4. The mode of blastocyst implantation varies widely among different species. Research on human blastocyst implantation is extremely limited because of ethical concerns. So it is imperative to extrapolate the data obtained from non-human species to understand human uterine receptivity and blastocyst implantation. This special situation necessitates extensive comparative studies between species, and thus, collaborative studies are essential in this program. Given the advent of new technologies (such as establishment of the epoch-making uterine cell culture systems, development and availability of new reagents such as growth factors and their antibodies and messages) during the last few years and the persistent need to improve the pregnancy rate in human in vitro fertilization clinics, there are still opportunities for research on this central problem in the clinically-assisted establishment of a pregnancy to lead to rapid progress. Such progress will depend upon the use of newly developed molecular and cellular biological technologies and, particularly, upon a coordinated, collaborative effort among researchers of different disciplines who are highly committed to investigating this problem. The outcome of this Program's effort to improve pregnancy rates in humans as well as domestic animals by prevention of implantation failure will benefit the clinical and applied fields of the reproductive sciences. Knowledge gained from this Program on uterine receptivity for blastocyst implantation will yield new information about defined markers that can be used to indicate whether the uterus is receptive or refractory for blastocyst implantation. Such knowledge is crucial for selecting the optimal timing to facilitate the establishment of pregnancy. Thus, there are both basic and applied scientific needs to clearly understand the mechanism by which the uterus become receptive to blastocyst implantation. This Cooperative Program will lead to protocols to detect the receptivity of the uterus and will provide a better understanding of the mechanisms involved in the sequential interactions between the embryo and the uterus leading to successful blastocyst implantation. Since the outset of this Program two and a half years ago, the Principal Investigators have identified several molecules that appear on the uterine luminal epithelium prior to and during blastocyst implantation. These molecules have temporal and spatial relationships with blastocyst implantation. However, markers identified in the animal model system must be confirmed in the human to be able to develop noninvasive measurement methods in humans. Species variability and the cross-reactivity of available reagents have made it clear that studies on human uterus are necessary to apply the information obtained in experimental animals to humans. Recent developments in human uterine investigations indicate that some molecular substances may serve as good markers for uterine receptivity. However, there is very little knowledge about the role in implantation. The understanding of human implantation must depend on studies on experimental animals from which biological samples at precise stages of pregnancy or a cycle can be obtained for analyses. When specific markers are identified in uterine endometrial biopsies, it is necessary to consider how the surgical perturbation encountered during tissue sampling would affect the physiological sequence of the endometrial function. Taking biopsies from the endometrium just prior to embryo transfer would likely perturb the endometrium where the transferred embryo is expected to implant. It is desirable to avoid the traumatic effects of invasive methods for sampling tissues to check uterine receptivity. It is, therefore, important to develop noninvasive methods to detect useful markers of uterine receptivity. Objectives and Scope The major objectives are identification and characterization of markers useful for indicating that the uterus is, or is going to be, receptive for blastocyst implantation; to clarify how these markers are involved in the implantation mechanisms; and to develop noninvasive methods to detect the markers. The following are some examples of research topics, but they are not to be viewed as exclusive and restrictive: o Identification of a marker molecule, for example, a growth factor, its receptor, or integrin, on the luminal epithelial surface of endometrium that appears and disappears in parallel with the initiation and termination of the receptive phase; o characterization of adhesion interactions between the apical surface of uterine luminal epithelial cells and trophoblast to identify a potential marker molecule; o ovarian steroid regulation of a marker molecule; o detection of a marker molecule or its metabolite in body fluid to develop a noninvasive method for the marker; o investigation of the role of a marker molecule in the process of implantation; o comparative study of animal and human uterine tissues to determine applicability of information obtained in the animal to human in terms of a marker molecule, its isoform, or a related molecule. SPECIAL REQUIREMENTS The NICHD invites applications both from current members of the Cooperative Program (competing continuation applications), and from prospective members (new applications). The minimal requirements for applicants are as follows (see also REVIEW CONSIDERATION below): o Competent, experienced principal investigators who are committed to this problem and who are willing to cooperate with the other Principal Investigators and the NICHD Research Coordinator; o access to properly managed animal colonies with breeding capabilities and/or access to existing human specimens or tissues subject to discard; o agreement to participate in Steering Committee meetings that will be held at least twice a year; o experience with analyzing, characterizing, localizing and/or measuring biological molecules and investigating the blastocyst implantation process. The following terms and conditions of the cooperative agreement award and details of the arbitration procedures pertaining to the scope and nature of the interaction between the NICHD and the participating awardees will be incorporated into the Notice of Grant Award and provided to the Principal Investigator and the institutional official at the time of award. These procedures will be in addition to the customary programmatic and financial negotiations that occur in the administration of grants. Terms and Conditions of Award Cooperative agreements are assistance mechanisms subject to the same administrative requirements as grants. The special Terms and Conditions of Award are in addition to, not in lieu of, otherwise applicable OMB administrative guidelines, HHS, PHS, and NIH grant regulations, policies and procedures, with particular emphasis on HHS regulations at 42 CFR Part 74 and 92. Indirect cost award procedures will apply to cooperative agreement awards in the same manner as for grants. Business management aspects of these awards will be administered by the NICHD Grants Management Office in accordance with HHS, PHS, and NIH grant administration requirements. 1. The Steering Committee The planning and implementation of the study will be done by a Steering Committee consisting of the Principal Investigators from each of the participating sites, one NICHD staff member from the Reproductive Sciences Branch who will serve as Research Coordinator, and a nonvoting, independent Chairperson. To ensure impartiality, the independent Chairperson will be a scientist of national stature who is not participating as a Principal Investigator and who is mutually acceptable to the participants. The Steering Committee will meet at least twice a year. 2. Awardee Responsibilities and Rights The primary responsibilities of the awardees are: o Determine experimental approaches o Design protocols o Conduct experiments o Analyze and interpret the results o Present results and plans at Steering Committee meetings o Publish results o Modify, delete or add protocols within the scientific scope of the project o Accept and participate in the cooperative nature of the group process. Awardees will retain custody of, and primary rights to, their data developed under the award, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. 3. The degree of programmatic/scientific assistance by the NICHD staff Research Coordinator includes: o Participation in the development of optimal approaches and protocol designs (and adjustments of protocols and approaches when needed). The Research Coordinator will assist and facilitate the process, rather than direct it. o Assistance and review of all phases of the study to assure consistency of protocol compliance, to improve and strengthen cooperation between the sites, and to help redirect efforts, modifying or terminating a site, if necessary, when performance requirements are not met. In the event of disagreement among participants, the Research Coordinator will assist in forming an arbitration panel acceptable to participants (see below). o Participation in data analyses, interpretation and, when warranted, publication of study results. 4. Arbitration When agreement between an awardee and NIH staff cannot be reached on scientific/programmatic issues that may arise after the award, an arbitration panel will be formed. The panel will consist of one person selected by the Principal Investigator(s), one person selected by NICHD staff, and a third person selected by these two members. The decision of the arbitration panel, by majority vote, will be binding. This special arbitration procedure in no way affects the right of an awardee to appeal an adverse action in accordance with PHS regulations at 42 CFR Part 50, Subpart D, and HHS regulations at 45 CFR Part 16. 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 subgroups 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 new policy results from the NIH Revitalization Act of 1993 (Section 4928 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 reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Program staff may also provide additional information concerning the policy (see INQUIRIES). LETTER OF INTENT Prospective applicants are asked to submit, by January 5, 1996, 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 a subsequent application, the information that it contains allows NICHD staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: Dr. Koji Yoshinaga Center for Population Research National Institute of Child Health and Human Development Building 61E, Room 8B01 6100 Executive Boulevard, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-6515 FAX: (301) 496-0962 Email: yoshinak@hd01.nichd.nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 5/95) is to be used in applying for these cooperative agreements. These forms are available at most institutional offices of sponsored research; from the Office of Grants Information, Division of Research Grants, National Institutes of Health, 6701 Rockledge Drive, Room 3034, MSC 7762, Bethesda, MD 20892-7762, telephone 301/710-0267, email: girg@drgpo.drg.nih.gov. Content of Applications A response to this Request for Applications should include: o A description of the capabilities of the site to meet or exceed the minimal requirements (see SPECIAL REQUIREMENTS above). o A proposed four-year research plan that should be the applicant investigator's perception of the study and of his/her cooperative role. This plan should demonstrate the investigator's knowledge, ingenuity, practicality, and commitment to identify, characterize, and quantitate a marker(s) of the receptive uterus for blastocyst implantation. o All essential information should be included in the body of the application rather than in the Appendix. o Current members who wish to submit competing continuation applications should discuss the significant progress they have made in this Program and may wish to indicate how they met any special cooperative agreement terms and conditions of their awards including their interactions with other investigators and the Research Coordinator if appropriate. In order to address these aspects more clearly, current members may, if they so choose, up to five additional pages in the Progress Report section of their application. Budget Since the final protocol(s) for this study will not be exactly known at the time of submission of the application, the budget request should be based on the plan proposed by the applicant and should reflect the scope of the project. The requested budget should not be in excess of the amount generally requested for a regular research grant. Budgets should not request annual increases for future years of more than four percent. Include estimates for staffing needs, although it is expected that some modification will be needed once the final research protocol(s) have been developed. The budget must also include estimates of travel expenses for two meetings of two days each of the Steering Committee per year. The first meeting will be a planning meeting held in Bethesda, Maryland in December 1996. Applications must be identified by typing in the RFA number, HD-95-018, and the RFA Title, MARKERS OF UTERINE RECEPTIVITY FOR BLASTOCYST IMPLANTATION, on line 2 of the face page of the application form and the YES box must be checked. In addition, the RFA label available in the PHS 398 (rev. 5/95) 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. 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 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 Applications must be received by February 8, 1996. 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 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. Timetable Letter of Intent Receipt Date: January 5, 1966 Application Receipt Date: February 8, 1996 NACHHD Council Date: September 20, 1996 Earliest Award Date: December 1, 1996 REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the DRG and for responsiveness by NICHD staff. Incomplete applications will be returned to the applicant without further consideration. Any application that does not meet the minimum requirements (see SPECIAL REQUIREMENTS above) of this RFA will be judged to be unresponsive to this RFA and will be returned to the applicant. 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. As part of the initial merit review, all applications will receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed, assigned a priority score, and receive a second level review by the National Advisory Child Health and Human Development Council. Review Criteria In addition to the usual NIH criteria for scientific merit, evaluation of the applications will be based upon the following: 1. Qualifications, experience and commitment of key personnel: o Scientific and administrative abilities of the Principal Investigator and other team members. o Knowledge and experience in areas relevant to the conduct of the experiments proposed. o Commitment of time for the proposed study and stated willingness to work and collaborate with other sites and the NIH in the manner summarized in this RFA. 2. Protocols and Procedures o Appropriateness of the application to the objectives of the study as outlined in this RFA. o Scientific and technical merit of the proposed research. o Where human subjects are involved, 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 human subjects will also be evaluated. 3. Facilities and Management o Availability of resources necessary to perform the proposed research. o Adequacy of administrative and technical capabilities. o Adequacy of animal facilities and appropriateness of animal care management. o Institutional assurance to provide support to the study in such areas as fiscal administration, personnel management, space allocation, procurement, planning and budgeting. 4. Budgeting o Appropriateness of budget. 5. Human Subjects, Animal Welfare, Biohazards o The initial review group will also examine the provisions for the protection of human subjects and animals and the safety of the research environment. AWARD CRITERIA The anticipated date of award is December 1, 1996. Applications recommended by the NACHHD Council will be considered for award based upon scientific and technical merit as determined by peer review; program balance, including in this instance, sufficient compatibility of features to enhance the likelihood of a successful collaborative Program; and availability of funds. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcomed. Direct inquiries regarding scientific issues to: Koji Yoshinaga, Ph.D. Center for Population Research National Institute of Child Health and Human Development Building 61E, Room 8B01 Bethesda, MD 20892-7510 Telephone: (301) 496-6515 FAX: (301) 496-0962 E-Mail: yoshinak@hd01.nichd.nih.gov Direct inquiries regarding fiscal matters to: Ms. Melinda Nelson Office of Administrative Management National Institute of Child Health and Human Development Building 61E, Room 8A17 Bethesda, MD 20892-7510 Telephone: (301) 496-5481 FAX: (301) 496-0915 E-Mail: 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 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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