Full Text HD-93-04 PATHOPHYSIOLOGY OF ENDOMETRIOSIS AND LEIOMYOMATA UTERI NIH GUIDE, Volume 21, Number 16, May 1, 1992 RFA: HD-93-04 P.T. 34 Keywords: Pathophysiology Reproductive Endocrinology Reproductive Physiology Growth Factors Pregnancy National Institute of Child Health and Human Development Office of Research on Women's Health Application Receipt Date: July 24, 1992 PURPOSE The National Institute of Child Health and Human Development (NICHD) and the Office of Research on Women's Health (ORWH) invite research grant applications for support of investigations into the biology and pathophysiology of endometriosis and leiomyomata uteri ("myoma"). Directives from the 102nd U.S. Congress included in Reports 102-121 of the House of Representatives and 102-104 of the Senate accompanying the NIH Appropriation Bill, H.R. 2707, for fiscal year 1992, have urged the NIH to address research efforts toward several diseases and conditions related to women's health including endometriosis and myoma. 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, Pathophysiology of Endometriosis and Leiomyomata Uteri, 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 "Healthy People 2000" (Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic for-profit and non-profit organizations, public and private. Minority individuals, persons with disabilities, and women are encouraged to apply. MECHANISM OF SUPPORT This RFA will use the NIH individual research 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 applications submitted in response to the present RFA may not exceed five years. 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. FUNDS AVAILABLE It is expected that up to five applications will be funded, within the total cost limit of $1,000,000 available for the first year. This level of support is dependent on the receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NICHD and the ORWH, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. BACKGROUND o Endometriosis Endometriosis is the growth of endometrial tissue outside of the uterine cavity, most often on the peritoneal lining of pelvic organs such as the ovaries and uterus. A common, poorly understood disorder, it can cause infertility and pain due to growth of implants, bleeding, and scarring. The cause is not known, although proposed etiologies have included retrograde menstruation, abnormal immune function, and a genetic contribution. Treatments are largely empirical. Medical treatment has been aimed at suppressing the natural menstrual cycle. Since endometriosis is the growth of endometrial tissue, it is responsive to sex steroids, such as the combined oral contraceptive (OC). Thus, OCs became a standard therapy. Some patients did not tolerate OCs well, while others desired fertility. In the late 1970s, danazol, a so-called "impeded" androgen, became available as an alternative to oral contraceptives. Danazol produces a low estrogenic state, thus inhibiting endometrial growth. It is considerably more expensive than oral contraceptives, and some women experience androgenic side effects. More recently, endometriosis has been treated experimentally with analogs of the hypothalamic hormone, gonadotropin releasing factor (GnRH), which normally stimulates the pituitary gland to secrete the gonadotropin hormones that stimulate the ovary. The analogs "turn off" the stimulation. Beyond, or sometimes instead of, medical therapy, surgery has been offered. Definitive treatment of endometriosis has historically consisted of radical surgery to remove the uterus, ovaries, and any other sites of endometrial implants. This treatment is not recommended for mild cases and for women who might wish to become pregnant. Modern advances have included use of improved lasers and laparoscopy to avoid major abdominal surgery. Still, the ablation of lesions does not always correlate with symptomatic relief or alleviation of infertility. Therefore, it has become a high-priority area for the NICHD and the ORWH to stimulate research into the etiology and pathophysiology of endometriosis, in search of leads for improved diagnosis and therapy. o Myoma Leiomyomata uteri are benign tumors of the muscular layers of the uterus. They are a frequent cause of abnormal uterine bleeding and the leading indication given for hysterectomy. Since they are estrogen dependent, they affect women of reproductive age for the most part. There appears to be a genetic component, but the cause is unknown. The relationship between myoma and infertility is not well defined, but there appears to be an association with early fetal wastage. In addition to bleeding and infertility, myomata can cause pelvic pain. The estrogen dependence of leiomyomata has led to empirical treatment with many of the same therapies as were mentioned above under endometriosis, including progestins, danazol, and GnRH analogs to prevent or oppose the action of estrogen. However, the long-term safety and efficacy of analogs have not been determined, the long-term hypoestrogenic state raises the risk of osteoporosis, and the tumors regrow promptly upon the cessation of treatment. For this reason, they are often used as an adjunct to facilitate surgery, rather than as definitive therapy. There is a great need for more knowledge about the process of myoma initiation and growth. If safe, long-term medical therapies were developed based on solid scientific rationales, thousands of women annually might be spared surgery, with resulting reduced morbidity and preservation of fertility. RESEARCH OBJECTIVES Areas that will be considered responsive to this RFA include, but are not limited to: o Mechanisms by which endometriotic lesions arise and proliferate; o Elucidation of effectors of myoma growth regulation, specific to leiomyomata uteri rather than tumorigenesis in general; o New approaches to intervention based on established responses of endometriosis or myoma cells to hormonal, immune, or growth factors; o Use of improved animal or cell culture model systems for the study of endometriosis or myoma relating to the above; o Elucidation of factors contributing to reduced incidence of clinical pregnancy in women with endometriosis or myoma. While applicants are encouraged to include a clinical research component, it is not the intent of this RFA to support clinical trials. Applications proposing clinical trials will not be considered responsive to this RFA. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements are required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. For the purpose of this RFA, investigations are limited to disorders occurring only in women. If minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of racial/ethnic group. In addition, racial/ethnic issues must be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information, as well as the limitation of studies to women, must be included in the form PHS 398 in Sections 1-4 of the Research Plan AND summarized in Section 5, Human Subjects. Applicants are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans [including American Indians or Alaskan Natives], Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups should be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. This definition is independent of "involvement" of human subjects (see below). The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. If the required information is not contained within the application, the application will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of minorities in a study design is inadequate to answer the scientific question(s) addressed AND the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional business offices; and from the Office of Grants Inquiries, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone (301) 496-7441. The RFA label available in the PHS 398 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 and number must be typed on line 2a 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 Westwood Building, Room 240 Bethesda, MD 20892** At the time of submission, two additional copies of the application must also be sent to: Laurance Johnston, Ph.D. Division of Scientific Review Institute or Division National Institute of Child Health and Human Development Executive Plaza North, Room 603 Bethesda, MD 20892 For courier delivery use: Rockville, MD 20852 Applications must be received by July 24, 1992. If an application is received after that date, it will be returned to the applicant. The Division of Research Grants (DRG) will not accept any application in response to this announcement 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed by NIH staff for completeness and responsiveness. Incomplete applications will be returned to the applicant without further consideration. If the application is not responsive to the RFA, NICHD staff will 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 may be triaged by a peer review group on the basis of relative competitiveness. The NIH will withdraw from further competition those applications judged to be non-competitive for award and notify the applicant Principal Investigator and institutional official. Those applications judged to be competitive will undergo further scientific merit review. Those applications that are complete and responsive will be evaluated in accordance with the criteria stated below for scientific/technical merit by a peer review group convened by the DRG. The second level of review will be provided by the National Advisory Child Health and Human Development (NACHHD) Council. Review criteria for RFAs are generally the same as those for unsolicited research grant applications. o scientific, technical, or medical significance and originality of proposed research; o appropriateness and adequacy of the experimental approach, methodology, and analysis 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 resources necessary to perform the research; o appropriateness of the proposed budget and duration in relation to the proposed research AWARD CRITERIA The anticipated date of award is September 30, 1992. Funding decisions will be based on initial review group and NACHHD Council recommendations, program relevance, 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 programmatic issues to: Donna L. Vogel, M.D., Ph.D Reproductive Sciences Branch Center for Population Research National Institute of Child Health and Human Development Executive Plaza North, Room 603 Bethesda, MD 20892 Telephone: (301) 496-6515 FAX: (301) 496-0962 Direct inquiries regarding fiscal matters to: Melinda Nelson Office of Grants and Contracts National Institute of Child Health and Human Development Executive Plaza North, Room 505 Bethesda, MD 20892 Telephone: (301) 496-5481 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 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 12374 or a Health Systems Agency review. .
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