LEIOMYOMATA UTERI: BASIC SCIENCE AND TRANSLATIONAL RESEARCH RELEASE DATE: November 18, 2002 RFA: HD-03-005 National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov/) National Institute of Environmental Health Sciences (NIEHS) (http://www.niehs.nih.gov/) Office of Research on Women's Health (ORWH) (http://www4.od.nih.gov/orwh/) LETTER OF INTENT RECEIPT DATE: March 14, 2003 APPLICATION RECEIPT DATE: April 14, 2003 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute of Child Health and Human Development (NICHD), the National Institute of Environmental Health Sciences (NIEHS), and the NIH Office of Research on Women's Health (ORWH) invite new and experienced investigators to submit research grant applications in basic science, environmental health science, and translational research with the goal of translating advances in our understanding of the molecular basis of leiomyomata uteri (uterine fibroids) into new therapies for prevention, treatment, and cure of this common benign gynecologic disorder. This solicitation focuses on basic science and translational research studies that are innovative in their approach to determine the complex molecular basis of this disorder. Results from this research are expected to have important applications for moving advances in basic science research from the laboratory to clinical practice. RESEARCH OBJECTIVES Background This initiative addresses the need to increase our knowledge and understanding about leiomyomata uteri and the biological processes that lead to their development and long-term sequelae. The objective is to strengthen research in this critical area of women's health, contribute to reducing the burden of this disease, and improve the quality of life for women affected with this disorder. Uterine leiomyomata constitute a significant public health concern. While uterine leiomyomata represent the most common gynecologic tumor in women, the mechanisms that initiate uterine leiomyoma growth and pathogenesis are not completely understood. Several studies estimate that 20 to 40 percent of reproductive age women have uterine leiomyomata and, according to some reports, they are diagnosed in African American women two to three times more frequently than in Caucasian women. This disorder is clinically important because it is a significant source of abnormal uterine bleeding, anemia, and pelvic pain. In addition to pain, uterine leiomyomata may press on adjacent structures, leading to difficulty with urination or defecation or dyspareunia. These symptoms frequently lead to various medical and/or surgical interventions. Surgical procedures are of primary concern, because uterine leiomyomata remain the leading indication for a hysterectomy in the United States. Thus, both the economic costs and effect on quality of life can be substantial. Increased emphasis on a condition that poses a serious reproductive threat for many women and represents a disproportionate burden for African American women can enhance our ability to preserve the fertility and reproductive health of all women. To address the need for increased attention in this area, NICHD collaborated with the ORWH in sponsoring a workshop in 1992 on "Abnormal Uterine Bleeding, Myomas and Infertility." At the workshop, experts defined and prioritized research needs. The presentations and discussions stimulated the development of ideas for new projects and, because of this meeting, the research community was made aware of the interest of NICHD in these areas. This workshop was followed by a Request for Applications on the Pathophysiology of Endometriosis and Leiomyomata Uteri (RFA-HD-93-04), resulting in the award of several new grants. In a subsequent workshop, convened in 1994, on "Alternatives to Hysterectomy--Bench to Bedside," funded investigators, along with outside experts, were brought together to discuss how evolving basic science could now provide a framework for more applied or clinical research. Topics included medical regimens, such as utilization of gonadotropin- releasing hormone (GnRH) analogs, antiprogestins, prostaglandin inhibitors, and conservative surgical approaches. This meeting demonstrated that while researchers have gained some insight into the mechanisms that mediate uterine leiomyoma development and growth, and some progress has been made, many challenges remain. On October 7-8, 1999, the NICHD in collaboration with NIEHS, ORWH, and the Public Health Service, Office of Women's Health, convened another conference, entitled "Women's Health and the Environment: The Next Century--Advances in Uterine Leiomyoma Research," to explore the state-of-the-science. The distinguished panel of speakers provided a review of the current approaches to the pathophysiology, mechanisms of tumor development, epidemiology, environmental influences, and clinical therapeutics related to uterine leiomyomata. A summary of the conference was published in Environmental Health Perspectives, 2000, 108 (S5) 769-773. In response to recommendations made at the conclusion of this conference, priority was placed on stimulating relevant research strategies focusing on promising and innovative studies that would continue to enhance our knowledge of uterine leiomyomata. These activities have formed the groundwork for assessing future research opportunities and complementing the ongoing commitment of NICHD, NIEHS, and ORWH to support research important to women's reproductive health. Research Scope The general scope of proposed studies could encompass determining the etiology, diagnostic criteria, and underlying pathophysiology deemed important for building a substantive knowledge base. Critical variables for uterine leiomyoma growth, such as hormonal stimulation, molecular and cytogenetic changes, differences in cell regulation, and the influence of exposures to environmental agents are areas for further assessment. Moreover, aspects of research such as preclinical studies, animal models, basic biological processes, genetic factors, and translational research are all potential avenues for further examination. This initiative is expected to increase our knowledge about the underlying mechanisms that will build a framework for strengthening the science base, improving clinical applications, and providing clues for more effective conservative management of this clinically relevant disorder. Examples of the scope of research topics considered responsive to this announcement include, but are not limited to, the following: o Initiation of a genome-wide screen to characterize the genetic liability for developing uterine leiomyomata, with particular emphasis on racial overexpression in African American women, twin-pair correlation, and familial predisposition; o Elucidation of the role of genetic alterations in the process of tumor transformation, correlating the cytogenetic and/or genomic abnormalities with phenotypic expression; o Development of surrogate animal models to assess the mechanism of leiomyoma formation and to screen for candidate therapeutic agents and prevention strategies; o Identification of the basic molecular and cellular processes and examination of the mechanisms by which estrogen and progesterone induce cell transformation and promote tumor growth or suppression. Clarification of the interaction between estrogen and progesterone and related growth factors; o Study of the potential role of selective estrogen receptor modulators (SERMs) on uterine leiomyoma development and growth. Further characterization of endocrine disrupters and their influence on the risk of uterine leiomyoma formation, including the effect of time of exposure (fetal, neonatal, pubertal or adult) and dose relationships on the initiation or exacerbation of uterine leiomyoma development; o Assessment of whether growth factor expression is the framework through which abnormal myometrial cellular and extracellular growth can be explored to clarify the interaction between estrogen/progesterone and growth factors and/or environmental exposures on uterine leiomyoma initiation and development; o Identification of noninvasive biomarkers to delineate molecular alterations at specific stages of tumor development and definition of molecular markers for uterine leiomyoma progression and recurrence; o Facilitation of collaborative molecular studies through the establishment of a tissue bank; o Development of new avenues for diagnostic and conservative treatment modalities that target relevant hormonal pathways for uterine leiomyoma formation, including the design of novel pharmaceutical agents directed at these pathways; o Examination of gene-environment relationships including an examination of genetic polymorphisms in key pathways and the effects of various environmental insults, such as the exposures to solvents, pesticides, water disinfection byproducts, and metals singly or in mixtures in the initiation or exacerbation of uterine leiomyoma. These studies may include transgenerational effects as well as developmental vulnerability. MECHANISM OF SUPPORT This RFA will use the NIH individual research project grant (R01) award mechanism. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2003. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. FUNDS AVAILABLE The NICHD intends to commit approximately $2 million [Direct plus Facilities and Administrative (F & A) costs] in FY 2003 to fund five to six new grants in response to this RFA. The NIEHS intends to commit up to $600,000 [Direct plus Facilities and Administrative (F&A) costs] in FY 2003 to fund up to two grants with an emphasis on the role of environmental exposures on the initiation or exacerbation of uterine leiomyoma. An applicant may request a project period of up to five years and a budget for direct costs of up to $250,000 per year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NICHD and NIEHS 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. ELIGIBLE INSTITUTIONS You may submit an application if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS Annual Investigator Meeting After initiation of the program, the NICHD will sponsor a meeting to encourage the exchange of information among investigators who participate in this program. In the preparation of the budget for the grant application, applicants should include travel funds for the meeting to be held in Bethesda, Maryland. Applicants should also include a statement in the applications indicating their willingness to participate in such a meeting. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about basic science and translational scientific/research issues or general RFA matters to: Estella Parrott, M.D., M.P.H. 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) 496-0962 Email: ep61h@nih.gov o Direct your questions about the role of environmental agents or environmental scientific/research issues to: Jerrold Heindel, Ph.D. Organs and Systems Toxicology Branch Division of Extramural Research and Training National Institute of Environmental Health Sciences 79 T.W. Alexander Drive 4401 Building Research Triangle Park, NC 27709 Telephone: (919) 541-0781 FAX: (919) 541-0781 Email: heindelj@niehs.nih.gov o Direct your questions about financial or grants management 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) 480-4782 Email: kh47d@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o 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 NIH staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Estella Parrott, M.D., M.P.H. 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) 496-0962 Email: ep61h@nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and five 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) The Center for Scientific Review (CSR) 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 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NICHD and NIEHS. Incomplete and/or non-responsive 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 NIH in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a second level review by the National Advisory Child Health and Human Development Council and the National Advisory Environmental Health Sciences 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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, you 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: o PROTECTIONS: 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. o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below.) o DATA SHARING: The adequacy of the proposed plan to share data. o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: March 14, 2003 Application Receipt Date: April 14, 2003 Peer Review Date: June 2003 Council Review: September 2003 Earliest Anticipated Start Date: September 30, 2003 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. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is 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 clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH-defined Phase III clinical trials that: a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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 that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this RFA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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 view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance Nos. 93.864 and 93.113 and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the 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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