COOPERATIVE PROGRAM ON TROPHOBLAST-MATERNAL TISSUE INTERACTIONS Release Date: April 24, 2001 RFA: RFA-HD-01-012 National Institute of Child Health and Human Development (http://www.nichd.nih.gov) Letter of Intent Receipt Date: June 15, 2001 Application Receipt Date: July 18, 2001 PURPOSE The National Institute of Child Health and Human Development (NICHD) invites applications from investigators willing to participate in the multisite Cooperative Program on Trophoblast-Maternal Tissue Interactions. This program will utilize the Cooperative Agreement mechanism. The primary goals of this program are: (1) to assist in establishing healthy pregnancies for women who have difficulty in conceiving because of implantation failure, and (2) to prevent/alleviate abnormal implantation that would endanger the mothers by resulting in preeclampsia or ectopic pregnancy, leading causes of maternal mortality in black women. In order to achieve these goals, it is expected that investigators will: (1) define the receptive state of the reproductive tract for blastocyst implantation, (2) characterize how normal and abnormal processes of implantation are regulated, (3) develop new diagnostic tests for physiological and pathological conditions of the endometrium and other parts of the reproductive tract, (4) develop noninvasive methods for detecting and preventing abnormal implantation, and (5) develop methods to prevent multiple pregnancies in assisted reproductive technology while a high pregnancy rate is maintained. It is anticipated that the participating investigators will cooperate in an interdisciplinary manner to achieve these goals. The ultimate beneficiaries of this program will be women who have difficulty in attaining healthy pregnancies because of implantation failure, and those who suffer from abnormal implantation. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of Healthy People 2010, a PHS- led national activity for setting priority areas. This Request for Applications (RFA) is related to one or more of the priority areas. Potential applicants may obtain Healthy People 2010 at http://www.health.gov/healthypeople. 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 This RFA will use the National Institutes of Health (NIH) Cooperative Research Project Grant (U01) award mechanism, an assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and stimulate the recipients activity by involvement in the activity and otherwise working jointly with the award recipients in a partner role, but it is not to assume direction, prime responsibility, or a dominant role in the activity. Details of the responsibilities, relationships, and governance of the studies to be funded under cooperative agreements are discussed below under Terms and Conditions of Award. FUNDS AVAILABLE The NICHD intends to commit approximately $1.5 million in total costs [direct plus Facilities and Administrative (F&A) costs] in FY2002 to fund up to five new grants in response to this RFA. An applicant may request a project period of up to five years and a budget for direct costs of up to $250,000 for the first year, excluding F & A costs on consortium arrangements. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NICHD provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. At this time, it is not known if competing renewal applications will be accepted and/or if this RFA will be reissued. RESEARCH OBJECTIVES Background The NICHD supported the initial National Cooperative Program on Markers of Uterine Receptivity for Non-human Blastocyst Implantation for four years between 1992 and 1996. This program was recompeted in 1996 and the program was renamed the National Cooperative Program on Markers of Uterine Receptivity for Blastocyst Implantation. This latter program is to end in November 2001. This current program has five sites (University of Delaware, University of Kansas, University of Illinois, Population Council and University of North Carolina). The purpose of the current program is to identify and characterize the molecules that indicate that the uterus is, or is going to be, receptive for blastocyst implantation, and to develop diagnostic methods to determine the state of the uterine endometrium as to its receptivity to blastocyst. The current group has identified several marker molecules that are expressed during the receptive period in animal models, and some of them are applicable to humans. In view of successful results and useful knowledge gained about endometrial function and molecules expressed under various physiological conditions, it was decided to expand the program scope to reflect clinical demands to detect, prevent, and/or alleviate abnormal implantation that would result in ectopic pregnancy and/or preeclampsia and endanger maternal health. A list of scientific publications by the current members of the National Cooperative Program on Markers of Uterine Receptivity for Blastocyst Implantation is available from the program contact listed under INQURIES, below. The goal of this Cooperative Program is to assist in establishing healthy pregnancies in women who have difficulty in conceiving because of implantation failure, and to prevent/alleviate abnormal implantation that would endanger the mothers health by resulting in preeclampsia or ectopic pregnancy. In order to investigate abnormal implantation processes such as ectopic implantation or preeclampsia, it is necessary to understand the normal implantation process and how abnormal implantation differs from normal. Objectives The major objectives of this RFA are the identification and characterization of maternal tissues that allow attachment and implantation of blastocyst, particularly molecules that are involved in interactions between trophoblast cells and maternal tissues and their components. It is hoped to identify specific molecules that are essential for the initial stages of blastocyst implantation, and clarify why implantation fails in the uterus of some infertile women. The goal of this program is to help establish healthy pregnancy in women. However, it is ethically unacceptable to study human implantation. Therefore, it is anticipated that investigators will study some aspects of human implantation using non-pregnant human reproductive tissues and animal model systems applicable to human implantation. This program will not support proposals on human embryos, human in vitro fertilization and embryo transfer. It is expected that investigators will: (1) identify specific molecules that are indicative of physiological/pathophysiological conditions of maternal tissue(s), and (2) investigate how these molecules interact with molecules on trophoblast in the processes of attachment, invasion, and development of tissues that are essential for establishment of pregnancy. To achieve this goal, applicants are requested to propose the study of a selected molecule(s) that is/are considered to play an important role(s) in the process of implantation. Ultimately, investigators participating in the program will be expected to study a different combination of molecules, systems, approaches, species of animal, and/or tissues from the other investigators. It is anticipated that selected meritorious applications will have investigations with unique expertise. Thus, these projects will complement one another. The selected investigators will form a team and, while each investigator will work on his/her project, each investigator will also study how his/her molecule or system is related to the molecules/systems of other members of the team. Research Scope Most ectopic pregnancies take place in the Fallopian tube. To prevent occurrence of ectopic pregnancy, one has to understand the mechanism of embryonic attachment to the tubal epithelium. Is the mechanism of embryonic attachment to the tubal luminal epithelial surface the same as that to the uterine luminal epithelium? Is tubal pregnancy unique to humans? If so, what is the genetic difference between humans and other species of animals? Is there a genetic difference between the cell surface of normal tubal epithelium and that of a woman who suffers from ectopic pregnancy? Can we attribute the reported health disparity in the occurrence of tubal pregnancy to expression of specific gene(s) on the tubal epithelium? Much information is needed in this research area. Interactions between trophoblast and maternal tissues in early stages of pregnancy involve interactions between trophoblast and maternal luminal epithelium, basement membrane, stromal cells, extracellular matrix components, and maternal blood vessels. Although there are various aspects to the interactions between trophoblast and maternal tissues, this program places special focus on gene expression and its regulation in the process of blastocyst implantation. Examples of research topics that fall within the scope of the program include, but are not limited to, the following: o identification of essential molecules that are expressed at the site of trophoblast-maternal tissue interactions, o investigation of the physiological or patho-physiological role of the identified molecule(s) in the normal, abnormal, or failing implantation process, o application of information obtained in animal models to human reproductive tissues to verify the significance of animal work, o detection and prevention of ectopic pregnancy based on regulation of identified molecules in the process of implantation, o development of animal models to increase the successful implantation rate of a transferred single embryo to provide useful information for prevention of multiple pregnancies in humans. Guidance and Management Structure The overall guidance and management of the program will be provided by a Steering Committee consisting of the Principal Investigators of 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. SPECIAL REQUIREMENTS Minimum Application Requirements The NICHD invites applications both from current members of the Uterine Receptivity Cooperative Program and from new applicants. Because of the change of the research scope, all applications will be considered new applications. The minimum requirements for applicants are as follows (see also REVIEW CONSIDERATIONS, below): o a competent, experienced Principal Investigator who is committed to investigation of these problems and who is 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. Meetings Principal Investigators are expected to attend two Steering Committee meetings of two days each per year. The first meeting will be a planning meeting held in Bethesda, Maryland in February 2002. Terms and Conditions of Award 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. 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. Facilities and administrative cost (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 Branch in accordance with HHS, PHS, and NIH grant administration requirements. 1. The Primary Rights and Responsibilities of the Awardees The primary rights and responsibilities of the awardees are to: 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. 2. NICHD Responsibilities NICHD Research Coordinator: The NICHD Research Coordinator will be a staff member of the Reproductive Sciences Branch. The Research Coordinator is a partner within the program, representing the government’s interest in the substantive work of the participating investigators. The primary role of the Research Coordinator is to facilitate the work of the investigators through the following activities: o participation in the development of optional 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, when performance requirements are not met. o participation in data analyses, interpretation and, when warranted, publication of study results. The above responsibilities are in addition to, not in lieu of, the levels of involvement normally required for program stewardship of grants. NICHD Project Officer: NICHD will appoint a Project Officer, apart from the Research Coordinator, who will: o have the option to withhold support to a participating institution if technical performance requirements are not met. o carry out continuous review of all activities to ensure objectives are being met. 3. Collaborative Responsibilities The planning and implementation of the studies will be done by a Steering Committee consisting of the Principal Investigators from each of the participating sites, the NICHD 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. 4. Arbitration Procedures 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 regulation 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 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 indicating 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 UPDATED NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research, published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html), a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH-defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable, and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender, and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the NIH Policy and Guidelines on the Inclusion of Children as Participants in Research Involving Human Subjects, published in the NIH Guide for Grants and Contracts, March 6, 1998, and available on the Internet at: http://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to review the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, telephone number, and e-mail address of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of this RFA. 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 plan the review. The letter of intent is to be sent to Dr. Koji Yoshinaga, at the address listed under INQUIRIES, below, by June 15, 2001. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research, on the Internet at http://grants.nih.gov/grants/funding/phs398/phs398.html, and 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, E-mail: grantsinfo@nih.gov. Application Instructions An application in response to this RFA 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 five-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 essential molecules expressed at the site of the trophoblast-maternal tissue interaction. o all essential information should be included in the body of the application rather than in the appendix. Budget Since the final protocol(s) for this study will not be 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. Budgets should not request annual increases for future years of more than three 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 requests for travel expenses for two meetings per year of the Steering Committee, lasting two days each. The first meeting will be a planning meeting held in Bethesda, Maryland in February 2002. Submission Instructions The RFA label available in the PHS 398 (rev. 4/98) application form must be stapled to the bottom of the face page of the application and must display the RFA number, HD-01-012. A sample RFA label is available at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. Please note this is the pdf format. 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 and number 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: CENTER FOR SCIENTIFIC REVIEW 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 should be sent to: L. R. Stanford, Ph.D. Director, Division of Scientific Review National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 5E03F, MSC 7510 Bethesda, MD 20892-7510 Rockville, MD 20852 (for express/courier service) Applications must be received by July 18, 2001. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept an application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. CSR 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and for responsiveness to this RFA by NICHD staff. Incomplete and/or nonresponsive applications will be returned to the applicant without further consideration. Applications that are complete and responsive to the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by the NICHD in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and may undergo a process in which only those applications deemed to have the highest scientific merit 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 The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for humans, animals or the environment, to the extent they may be adversely affected by the project proposed in the application. SCHEDULE Letter of Intent Receipt Date: June 15, 2001 Application Receipt Date: July 18, 2001 Peer Review Date: October/November 2001 Council Review: January 2002 Earliest Anticipated Award Date: February 1, 2002 AWARD CRITERIA Criteria that will be used to make award decisions include: o scientific merit (as determined by peer review), o availability of funds, o programmatic priorities, o sufficient compatibility of features to enhance the likelihood of a successful collaborative program. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Koji Yoshinaga, Ph.D. Center for Population Research National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8B01, MSC 7510 Bethesda, MD 20892-7510 Telephone: 301-496-6515 FAX: 301-480-2389 E-mail: ky6o@nih.gov Direct inquiries regarding fiscal matters to: Ms. Kathy Hancock Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17, MSC 7510 Bethesda, MD 20892-7510 Telephone: 301-496-5482 FAX: 301-402-0915 E-mail: kathy.hancock@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.864, Population Research. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. 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 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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