Full Text HL-92-07 COLLABORATIVE PROJECTS ON WOMEN'S HEALTH NIH GUIDE, Volume 21, Number 13, April 3, 1992 RFA: HL-92-07 P.T. 34, II Keywords: Cardiovascular Diseases Pulmonary Diseases Biomedical Research, Multidiscipl Human Reproduction/Fertility Physiology, Human National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: November 13, 1992 Application Receipt Date: December 9, 1992 PURPOSE The National Heart, Lung, and Blood Institute (NHLBI) invites the concurrent submission of small groups of scientifically related research project applications related to women's health issues. The goal of this program is to foster collaborative research in currently underinvestigated areas of women's health that relate to cardiovascular, lung, and blood diseases. The special feature of this program is the concurrent submission of research project grant applications by investigators who wish to collaborate on a common theme, but do not require extensive shared physical resources or core functions to conduct the research. In order to be responsive to this Request for Application (RFA), a minimum of three independent investigators with related research objectives may submit concurrent, collaborative, cross-referenced individual research project grant applications that address a common theme. The common theme may be one that spans the traditional boundaries of cardiovascular, lung, and blood research (e.g., thromboembolic events) or it may deal with a single disease or condition from several points of view (e.g., prevention, diagnosis, and treatment of chest pain). Investigators may submit applications for basic science and small clinical studies including biobehavioral and prevention research. Investigators are encouraged to propose studies that focus on both normal development and disease in various phases in women. Many studies demonstrate gender differences; this solicitation encourages research that compares women with women--of different ages, lifestyles, racial/ethnic groups, and socioeconomic status--to understand clinical attributes of normal and diseased conditions within the gender. 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 priorities. This RFA, Collaborative Projects on Women's Health, addresses several priority areas including heart disease and stroke, physical activity and fitness, and nutrition, as they relate to cardiovascular, lung, and blood diseases. 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 Domestic public and private, for-profit and non-profit institutions and organizations are eligible to apply in response to this RFA. Applications from women and minority investigators and institutions are encouraged. Awards will not be made to foreign institutions. MECHANISM OF SUPPORT The support mechanism for this program will be the traditional individual research project grant (R01). Applicants will plan and execute the research programs and are requested to furnish their own estimates of the time required to achieve the objectives of the proposed research project. Up to five years of support may be requested. At the end of the official award period, renewal applications may be submitted for peer review and competition for support through the unsolicited grant process of the NIH. It is anticipated that support for the present program will begin in July 1993. Administrative adjustments in project period and/or amount of support may be required at the time of the award. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded in connection with this RFA. Since a variety of approaches would represent valid responses to this announcement, a range of costs is expected among individual grants awarded. However, a collaborative group of R01s may not exceed $1,000,000 total requested costs (direct and indirect) each year, and the average total requested cost of applications within a group may not exceed the average total cost of NHLBI R01 grants ($220,000). Any equipment requested must be especially justified. Requests for expensive pieces of equipment are not encouraged. Collaborative arrangements involving other institutions must be strongly justified and should be discussed with program staff prior to submission of the applications. Individual investigators may request a small amount of funds, not to exceed 15 percent of direct costs for the time and effort contributed toward coordination of overall research and for that proportion of shared resources that is necessary for the research. FUNDS AVAILABLE Although the financial plans for fiscal year 1993 include $5,000,000 for the total costs of this program, award of grants pursuant to this RFA is contingent upon receipt of funds for this purpose. It is anticipated that up to six collaborative groups (15-25 R01 awards) will be supported under this program. The number and specific amount to be awarded will depend on the merit and scope of the applications received and on the availability of funds. RESEARCH OBJECTIVES Background The development and progression of cardiovascular, lung, and blood diseases in women represent areas of significant opportunity for research that may lead to improved strategies for prevention, diagnosis, and treatment. Cardiovascular diseases are the leading cause of death in women in the United States. A number of problems in clinical cardiology would benefit immediately from improved understanding of how gender affects the cardiovascular system. For example, chest pain in women presents a major diagnostic and therapeutic challenge. Although angiographic studies demonstrate that women have a lower prevalence of coronary artery disease, anginal type chest pain is more common in women. The low prevalence of coronary disease at certain ages renders currently available noninvasive diagnostic methods ineffective in many symptomatic women. The diagnosis of angina pectoris in women may be complicated by a higher prevalence of conditions associated with chest pain that, generally, have a favorable prognosis, such as mitral valve prolapse, variant angina, and microvascular angina. Nevertheless, women may suffer higher case fatality rates for myocardial infarction and have increased incidence of postinfarction angina and heart failure, despite a higher resting ejection fraction. It has been reported that women undergoing surgical revascularization have higher perioperative mortality and less favorable functional improvement, despite better left ventricular function and less apparent anatomic disease. Although recent studies suggest gender differences in the application of coronary artery catheterization and coronary artery bypass surgery, it may be difficult to dissociate age, comorbidity, and gender. Whether differential utilization by gender represents overuse in men, underuse in women, or appropriate use, and the extent to which this affects treatment and outcome are unknown. Several research groups have demonstrated gender differences in vascular reactivity. Coronary artery blood flow and its response to stress or exertion may underlie variations in the perception of chest pain and clinical manifestations of coronary heart disease (CHD), but this area has been largely unexplored. There is growing evidence that biologic differences identified between the genders may modulate the effect of standard risk factors for CHD. Sex hormone receptors have been identified in human coronary arteries, but their significance is unclear. In addition, although previous studies have shown that stress affects the levels of reproductive and other hormones, the relationship of stress to the mechanisms involved in atherogenesis in women is still largely unknown. Persons who engage in regular physical activity exhibit significantly lower rates of coronary heart disease and stroke, as well as lower prevalence of coronary risk factors such as glucose intolerance, hypertension, and low HDL cholesterol levels. The physiological synergy among the triad of smoking cessation, weight control, and physical activity appears to be particularly relevant for women, yet this area has been explored inadequately. Little is known about the specific personal, social, and environmental barriers to increased activity that are present at various life stages, or about methods for tailoring interventions to women of different ages, health status, and backgrounds. Chronic airways disease, which includes asthma and chronic obstructive pulmonary disease (COPD), is the most prevalent lung problem in the United States today, but its particular effects in women have received little attention. Asthma in pregnancy has been associated with an increased risk of gestational hypertension, preeclampsia, and significant excesses of preterm births, low birth weights, neonatal hypoxia, and neonatal mortality, yet the underlying mechanisms are poorly understood. Research on older asthmatic women indicates that steroid therapy is associated with a high risk for increased rate of bone loss, but the long-term risks and benefits of this treatment are unknown. COPD is largely a smoking-related disorder. Women smokers with early signs of COPD have been found to exhibit substantially higher airways reactivity than men. The reasons why women also have relatively more difficulty quitting smoking, and gain more weight when they do quit, remain unknown. In the area of blood diseases, there are many unexplored questions about thrombotic and antithrombotic processes that take place during various phases of a woman's life, including puberty, menopause, and pregnancy. Clinical decisions about anticoagulant and fibrinolytic therapy for women would benefit from more accurate information about gender-related differences in response to these therapies. Important questions exist concerning such topics as anticoagulation following surgery to prevent deep venous thrombosis and pulmonary embolism, anticoagulation during pregnancy, and fibrinolytic therapy for older women. Further research is also needed on thrombosis and hemostasis in specific subpopulations of women, such as those with sickle cell disease or systemic lupus erythematosus. The hematopoietic microenvironment influences growth and differentiation of hematopoietic cells. Several aspects of the hematopoietic process are prime targets for questions pertaining to the influence of gender and possible regulation by sex and other hormones. Newer evidence suggests that the marrow is intimately related to bone, its surrounding tissue, and that bone formation may influence marrow development. Thus, the elucidation of the interrelationships among sex hormones, bone, and marrow may provide insight into the process of blood cell formation, bone development and maintenance, and osteoporosis. Examples of Research Areas Examples of research that would be responsive to this RFA are given below. These research topics are intended to provide a perspective on the scope of research that would meet the purpose of this program. It is not required that all or any of them be included in a particular group of applications. Investigators are encouraged to consider other topics relevant to this program. o Assessment of myocardial perfusion and metabolism in women with the goal of distinguishing, among women with ischemia-like chest pain, those in whom symptoms are an early manifestation of myocardial ischemia. o Determination of the location and concentration of vascular hormone receptors in women and/or female animal models and evaluation of receptor-mediated changes in vasomotor tone o Elucidation of the mechanisms that mediate the effects of stress on lipid metabolism and atherogenesis, such as the relationship between stress, ovarian dysfunction, and premenopausal myocardial infarction. o Development and evaluation of interventions to promote physical activity to enhance cardiovascular and pulmonary fitness among adult women at various life stages, such as entry into the work force, parenthood, and retirement. o Evaluation of the effect of asthma and its treatment on pregnant women, the developing fetus, and perinatal outcome; examination of the benefits and risks of steroid therapy for asthma in postmenopausal women who have been treated with steroids for various lengths of time. o Investigation of mechanisms that contribute to increased airways responsiveness in women; studies of synergistic effects of airways reactivity, cigarette smoking, and environmental/occupational exposures in women. o Determination of whether or not aspects of nicotine dependence affect smoking cessation rates in women and whether or not age, life stage, physical activity, and marital, health, racial/ethnic, and socioeconomic status differentially affect cessation rates. o Elucidation and exploration of reproductive problems in women with sickle cell disease (SCD), e.g., specific cause of menarchial delay, effect of SCD on conception and pregnancy outcome. o Investigation of thromboembolic events as a function of a woman's normal development and of life stages such as pregnancy and postmenopause; determination of factors that influence response to thrombolytic agents and anticoagulants in women; and development of safe and effective anticoagulants for use during pregnancy. o Investigation of the role and effect of sex hormones on the hematopoietic microenvironment and the subsequent growth and differentiation of hematopoietic cells Exclusions This RFA is intended to support individual research grants. Studies in men will not be responsive to this RFA. Large population-based studies, such as epidemiologic surveys and clinical trials, will be considered unresponsive to this announcement. SPECIAL REQUIREMENTS Upon initiation of the program, annual meetings will be held in Bethesda, Maryland, to encourage an exchange of information and ideas among investigators who participate in this program. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF MINORITIES IN RESEARCH STUDY POPULATIONS This RFA focuses on women. NIH and ADAMHA policy is that applicants for research grants are required to include minorities in study populations so that research findings can benefit all persons at risk of the disease, disorder, or condition under study. Special emphasis should be placed on the need for inclusion of minorities in studies of diseases, disorders, and conditions that disproportionately affect them. If minorities are excluded or are inadequately represented in clinical research, a clear, compelling rationale for exclusion for inadequate representation should be provided. The composition of a proposed study population must be described in terms of racial/ethnic group, together with a rationale for its choice. In addition, racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. Information should be included in the form PHS 398 in Section 2, 1-4 of the research plan AND summarized in Section 2, 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 includes human biomedical and behavioral studies of etiology, epidemiology, (and preventive strategies), diagnosis, or treatment of diseases, disorders, or conditions, including but not limited to clinical trials. 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 minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. If the application does not contain the required information, it will be returned. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of minorities 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 will be 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. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes identification of other participating investigators and any other institutions, and a descriptive title. The NHLBI requests such letters only for the purpose of providing an indication of the number and scope of applications to be received and, therefore, usually does not acknowledge their receipt. A letter of intent is not binding, and it will not enter into the review of any application subsequently submitted, nor is it a necessary requirement for application. This letter of intent is to be received no later than November 13, 1992, and is to be sent to: Dr. Charles Turbyfill Review Branch Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 553 Bethesda, MD 20892 APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 9/91) is to be used in applying for these grants. This form is available in the applicant institution's office of sponsored research or business office. It may also be obtained from the Office of Grants Inquiries, National Institutes of Health, Room 449, Westwood Building, Bethesda, MD 20892. In preparing the application, it is important that the points identified in the section on REVIEW CONSIDERATIONS in this announcement are addressed. The new page limitation requirements must be observed. However, an additional two pages will be allowed to describe the collaborative arrangements in terms of the science and mechanisms for collaboration. Applicants should contact one of the program administrators listed under INQUIRIES to seek clarification or discuss any questions related to this announcement. To identify the application as a response to this RFA, Check "YES" on Item 2a of page 1 of the application and enter the title, "Collaborative Projects on Women's Health" and the RFA number HL-92-07. THE RFA LABEL ENCLOSED WITH THE PHS 398 FORM MUST BE AFFIXED TO THE BOTTOM OF THE FACE PAGE OF THE ORIGINAL APPLICATION. FAILURE TO USE THIS LABEL COULD RESULT IN DELAYED PROCESSING OF THE APPLICATION. Each group of applications must include a succinct description of the scientific relationship among the group of R01s; plans for collaboration, interaction, and communication among investigators in the group of applications; and the name of the individual responsible for organizing and maintaining effective collaboration. In the preparation of the budget for the grant application, applicants should request travel funds for a two-day meeting each year to be held in Bethesda, Maryland. Applicants should also include a statement in the application indicating a willingness to participate in such meetings. Send or deliver the completed application and three signed, exact photocopies in single packages boxed together to the following office, making sure that the original applications with the RFA label attached are on top and bound together: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892 SEND AN ADDITIONAL TWO COPIES OF THE APPLICATIONS IN A SINGLE PACKAGE TO DR. CHARLES L. TURBYFILL AT THE ADDRESS LISTED UNDER LETTER OF INTENT. IT IS IMPORTANT TO SEND THESE TWO COPIES AT THE SAME TIME AS THE ORIGINAL AND FOUR COPIES ARE SENT TO THE DIVISION OF RESEARCH GRANTS. OTHERWISE THE NHLBI CANNOT GUARANTEE THAT THE APPLICATION WILL BE REVIEWED IN COMPETITION FOR THIS RFA. Applications must be received by December 9, 1992. An application received after this date will be returned to the applicant. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for responsiveness to the objectives of this RFA. If an application or group of applications is judged unresponsive, the application(s) will be returned to the applicant. If an application submitted in response to this RFA is identical to or substantially the same as one already submitted to the NIH for review in the same cycle, the principal investigator will be asked to withdraw the pending application before the new one is accepted. Simultaneous submission of identical applications will not be allowed. Applications judged to be responsive will be reviewed for scientific and technical merit by an initial review group that will be convened by the Division of Extramural Affairs, NHLBI, solely to review these applications. This initial review will include a triage. The NHLBI will withdraw from further consideration applications judged to be noncompetitive and promptly notify the Principal Investigator and the official signing for the applicant organization. Those applications judged to be competitive will be further evaluated for scientific and technical merit by usual peer review procedures. Each application will receive a priority score based upon review criteria listed below. Review Criteria: Factors to be considered in the evaluation of each application will be similar to those used in review of traditional research project grant applications and, in addition, will include overall proposed collaboration. Major factors to be considered in the evaluation of applications will include: 1. Scientific merit of the proposed projects, including innovation, originality, and feasibility of the approach, and adequacy of the experimental design; 2. Competence of the investigators to accomplish the proposed research goals, their commitment, and the time devoted to the program; 3. Integration of the component R01s into an enterprise with a common theme and adequate plans for collaboration, interaction, and communication of information among participating investigators; 4. Adequacy of facilities for performance of the proposed research, including laboratory facilities, proposed instrumentation and, when needed, data management systems; 5. Appropriateness of the budget for the proposed project. AWARD CRITERIA The anticipated date of award is July 1993. Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program needs and balance, and the availability of funds. INQUIRIES Inquiries regarding this request for applications may be directed to the following program administrators: Patrice Desvigne-Nickens, M.D. Division of Heart and Vascular Diseases National Heart, Lung, and Blood Institute Federal Building, Room 3C06 Bethesda, MD 20892 Telephone: (301) 496-1081 FAX: (301) 480-6282 Carol Vreim, Ph.D. Division of Lung Diseases National Heart, Lung, and Blood Institute Westwood Building, Room 6A16 Bethesda, MD 20892 Telephone: (301) 496-7208 Fax: (301) 496-9886 Carol Letendre, Ph.D. Division of Blood Diseases and Blood Resources National Heart, Lung, and Blood Institute Federal Building, Room 516A Bethesda, MD 20892 Telephone: (301) 496-8966 Fax: (301) 402-1622 Elaine Stone, Ph.D., M.P.H. Division of Epidemiology and Clinical Applications National Heart, Lung, and Blood Institute Federal Building, Room 604A Bethesda, MD 20892 Telephone: (301) 496-3503 Fax: (301) 480-1357 For fiscal and administrative matters, contact: Thomas Turley Division of Extramural Affairs National Heart, Lung, and Blood Institute Westwood Building, Room 4A12 Bethesda, MD 20892 Telephone: (301) 496-7255 Fax: (301) 402-1200 AUTHORITY AND REGULATIONS These programs are described in the Catalog of Federal Domestic Assistance numbers: 93.837, Heart and Vascular Diseases Research; 93.838, Lung Diseases Research; 93.839, Blood Diseases and Resources Research. Awards will be made under the authority of the Public Health Service Act, Section 301 (42 USC 241) and administered under PHS grants policies and Federal regulations, most specifically 42 CFR Part 52 and 45 CFR Part 74. This program is not subject to the intergovernmental review requirements of Executive Order 12372, or to Health Systems Agency review. .

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