Full Text HL-93-05 EFFECTS OF SEX HORMONES ON CORONARY ARTERY REACTIVITY NIH GUIDE, Volume 21, Number 42, November 20, 1992 RFA: HL-93-05-H P.T. 34 Keywords: Cardiovascular Diseases Hormones Steroids Physiology, Human Pathophysiology National Heart, Lung, and Blood Institute Letter of Intent Receipt Date: February 1, 1993 Application Receipt Date: April 27, 1993 PURPOSE The Division of Heart and Vascular Diseases invites grant applications for up to five years of support for research into the roles of sex hormones in the physiology and pathophysiology of the coronary vasculature. The ultimate goal is to develop insights into therapeutic approaches for reducing the higher incidence of coronary diseases in men and post-menopausal women than pre-menopausal women. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Effects of Sex Hormones on Coronary Artery Reactivity, is related to the priority area of heart disease and stroke. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (telephone 202-783-3238). 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. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (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 Approximately $1.5 million in total cost will be provided for the first year of support for the entire program. It is anticipated that six new grants will be awarded under this program. 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 plan of the National Heart, Lung, and Blood Institute (NHLBI), awards pursuant to this RFA are contingent upon the availability of funds for this purpose. Administrative adjustments in project period and/or amount of support may be required at the time of the award. Since a variety of approaches would represent valid responses to this announcement, it is anticipated that there will be a range of costs among individual grants awarded. RESEARCH OBJECTIVES Background Recent studies reveal that temporary ischemia can occur, not only as a result of organic obstruction of the coronary artery, but also as a result of vasoconstriction and vasospasm. There is evidence that in many blood vessels, the endothelium as well as the vascular smooth muscle plays an active role in the control of vascular reactivity. The regulation of vascular reactivity, especially in the coronary arteries, may have a significant effect on vasospasm and the development of coronary vascular disease. Gender is one of the major risk factors for the development of coronary artery disease. Epidemiological studies show that young men are at higher risk than young women and that this prominent difference decreases in post-menopausal women. Involvement of sex hormones in vascular reactivity has been suggested frequently but clear evidence for a mechanism is lacking. Gender differences in vascular reactivity have been demonstrated by several research groups which suggest that the function of the endothelium and vascular smooth muscle are sexually differentiated and modulated by sex hormones. In these studies, a number of vessel segments from female and male animals treated with estrogen relaxed significantly more in response to both endothelium-dependent and endothelium-independent vasodilators than did ring segments from male or female animals treated with testosterone. In other studies, the tension generated by the vascular smooth muscle in response to the vasoconstrictors was greater in aortas from male than female rats. Moreover, removal of the endothelium and treatment with testosterone increases the responsiveness of the aorta of female rats. These observations suggest that the endothelium of male rats has a lesser capacity to inhibit contractions of the underlying vascular smooth muscle, possibly because it releases less endothelium-dependent relaxation factors under basal conditions. The expression of gender differences in vascular responses, however, depends on the vessel itself. Although several studies have demonstrated that coronary vessels from male animals show greater vascular reactivity, the degree to which coronary smooth muscle and the endothelium are sexually differentiated and modulated by sex hormones remains to be determined. It has been suggested that one of the protective effects of estrogens may be mediated through several systemic and local processes which include the direct and indirect effects of estrogens on structural elements of the vessel wall. Limited but significant data have identified the presence of androgen, progesterone and estrogen receptors in the coronary vasculature in experimental animals and progesterone receptors have been identified in coronary arteries of men. However, no attempt has been made to see whether there is a sex difference in the distribution and density of steroid binding sites. These results can only be viewed as qualitative information regarding the existence of hormone-specific target cells. In fact, identification of steroid hormone receptors in a potential target tissue does not necessarily establish physiological function. Receptor concentration is influenced by hormonal stimulation, sex, maturation, aging, and probably many other factors. These variations should be taken into consideration while evaluating the effects of sex hormones on the coronary vasculature. While recent studies have suggested that androgen and estrogen may modulate specific functions of aortic smooth muscle cells and that elevations in circulating concentrations of endogenous estrogen may influence the function of vascular endothelial or smooth muscle cells of the coronary artery, a correlation between steroid hormone receptors and hormonal modulation of cell function in the coronary vasculature still needs to be determined. Also, the role of the coronary reactivity should be evaluated in mature and immature animals of both sexes in terms of its morphological, pharmacological, and biophysiochemical characteristics. Sex hormones interact with the sympathetic nervous system at the peripheral level. Testosterone and estrogen have been shown to inhibit norepinephrine uptake and inactivation in isolated hearts of rats. Also, gender differences have been described in the distribution of endogenous catecholamines and in alpha receptor affinity. These data suggest that sympathetic control of the vascular reactivity exhibits a dimorphic pattern due to the action of sex hormones. The coronary circulation is predominately regulated by the sympathetic nervous system. Physiological stress such as exercise and hypoxia increases the sympathetic activity of the heart. Whether or not the coronary vascular bed responds to these stimuli in a sexually differentiated manner is still unclear. The evaluation of the interaction between the sympathetic mechanism and the sex hormones in this specific vascular bed will certainly provide important information regarding the mechanisms underlying coronary vascular disease under normal and stressful conditions in men and women across all ages. Objectives and Scope All applications must be focussed on the role of the sex hormones on coronary reactivity. The spectrum of experimental approaches considered responsive to this RFA includes in vivo and ex vivo studies of coronary vascular reactivity, co-culture techniques to elucidate cell to cell interaction, cell receptor density, as well as molecular pharmacological approaches that will enhance our understanding of how sex hormones regulate coronary vascular cell function. Proposed Research Examples of research projects are given below, however, these are provided for illustrative purposes only. Applicants may consider other projects that may contribute to the goals of this initiative, but are not included in this list. o Identification of the distribution and density of sex hormone receptors on the coronary vessels under different sex-, age- and cycle-related conditions. o Evaluation of the correlation between sex hormone receptors and hormonal modulation of cell function. o Differentiation between acute and chronic effects of sex hormones on coronary reactivity. o Evaluation of the expression of sexual dimorphism in coronary vascular reactivity which is controlled by the sympathetic nervous system under different physiological conditions. o Identification of the cellular and molecular mechanisms modulated by sex hormones. SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH policy is that applicants for NIH clinical research grants and cooperative agreements will be required to include minorities and women on 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 should 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. If women or 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 gender. In addition issues of gender should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information should 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 adequate numbers of women. For the purpose of this policy, clinical research includes human biomedical and behavioral studies of etiology, epidemiology, prevention (and prevention 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 women when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the application will not be accepted for review. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women 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, by February 1, 1993, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of subsequent applications, the information that it contains is helpful in planning for the review of applications. It allows NHLBI staff to estimate the potential review workload and to avoid conflict of interest in the review. The letter of intent is to be sent to: Review Branch Chief, Centers and Special Projects Section Division of Extramural Affairs National Heart, Lung and Blood Institute Westwood Building, Room 553A Bethesda, MD 20892 APPLICATION PROCEDURES The research grant application for PHS 398 (rev. 9/91) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and may be obtained 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, to identify the application as a response to this RFA, Check "YES", enter the title "Effects of Sex Hormones on Coronary Artery Reactivity", and the RFA number HL-93-05-H on Line 2a of the face page of the application. Send or deliver a signed, typewritten original of the application, including the checklist, and three signed photocopies to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** Send two additional copies of the application to the Chief Centers and Special Projects Section, at the address listed under LETTER OF INTENT. It is important to send these two copies at the same time as the original and three copies are sent to the Division of Research Grants (DRG). Otherwise, the NHLBI cannot guarantee that the application will be reviewed in competition for this RFA. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. Applications must be received by April 27, 1993. If an application is received after that date, it will be returned to the applicant without review. The 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. Upon initiation of the program, the Division of Heart and Vascular Diseases will sponsor periodic meetings to encourage exchange of information among investigators who participate in this program, and to stimulate collaboration. Applicants should request additional travel funds for a one-day meeting each year, most likely to be held in Bethesda, Maryland. Applicants should also include a statement in their applications indicating their willingness to participate in these meetings. 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, NHLBI 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 an NHLBI 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 an appropriate peer review group convened by the NHLBI. The second level of review will be provided by the National Heart, Lung, Blood Advisory Council. Review criteria for RFAs are generally the same as those for unsolicited research grant applications. o the novelty, originality and feasibility of the approach and the adequacy of the experimental design o the competence of the principal investigator and collaborators to accomplish the proposed research, and the commitment and time they will devote to the project o the suitability of the facilities to perform the proposed research, including laboratories, instrumentation and data management systems o the appropriateness of the requested budget and duration for the proposed research o adequate plans for interaction and communication of information and concepts among investigators involved in collaborative studies AWARD CRITERIA Although multidisciplinary approaches are encouraged, it is not the intent of this announcement to solicit applications for large studies that would encompass a variety of independent project, i.e., program projects. This program will not support clinical trials or large epidemiological studies. In general, funds will not be provided for the purchase and installation of expensive, new equipment. Awards under this announcement to foreign institutions will be made only for research of very unusual merit, need and promise, and in accordance with Public Health Service policy governing such awards. The anticipated date of award is December 1, 1993. INQUIRIES Inquiries regarding this announcement may be directed to: Dr. Isabella Liang Cardiac Diseases Branch 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 Direct inquiries regarding fiscal and administrative matters to: Mr. William Darby Grants Operations Branch Division of Extramural Affairs National Heart, Lung and Blood Institute Westwood Building, Room 4A11 Bethesda, MD 20892 Telephone: (301) 496-7536 FAX: (301) 402-1200 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.837, Heart and Vascular Diseases. 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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