PHYSIOLOGICAL ROLE OF THE ADRENAL ANDROGEN, DHEA, IN AGING NIH GUIDE, Volume 21, Number 40, November 6, 1992 PA NUMBER: PA-93-015 P.T. 34 Keywords: Aging/Gerontology Endocrine System Immune System Hormones National Institute On Aging PURPOSE The National Institute on Aging (NIA) has responsibility for extramural programs of research and training in immunology and endocrinology related to aging. This support has resulted in a better understanding of the behavior of, and specific changes in, various components of the immune and endocrine systems in aging. It is well recognized that changes in the immune and endocrine systems during aging have profound influences on homeostatic mechanisms of the body. Some of these changes may be a result of "normal aging;" others may be due to environmental factors, such as stress and disease. Steroid, peptide, and eicosenoid hormones secreted from endocrine tissues are known to influence the immune system. Conversely, some cytokines, interferons and interleukins, modulators of immune system function, have profound regulatory effects on the endocrine system. Since both the immune and some components of the endocrine systems decline with advancing age, it is of interest to explore and delineate regulatory interactions between the immune and endocrine systems in the aging mammal. The purpose of this program announcement is to focus on the physiological role of the adrenal steroidal androgen precursor, dehydroepiandrosterone (DHEA), in aging. DHEA, and its sulfated form, DHEAS, decrease steadily with age in both animals and humans. This decline may represent a biomarker of biological aging. DHEA/DHEAS levels have also been found to be depressed in a number of disease states (eg., systemic lupus erythematosis (SLE), AIDS, cancer, diabetes, cardiovascular disease) and during stress and trauma (e.g., burns, surgery). Administration of DHEA has been shown to inhibit the development of obesity and to protect against carcinogenesis in mice. Recent research has demonstrated that the administration of physiologic doses of DHEA/DHEAS to aged mice may reverse the age-related immunological anergy by permitting the production of antibody and cellular responses at levels comparable to those of fully immunocompetent mature adult mice. The pattern of the lymphokine production was also restored to that of normal mature mice. DHEAS administration also has been shown to counteract the inflammatory production of Interleukin-6 and the effects of corticosteroids following stress and trauma. ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign and domestic, 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. Applicants for K- and F-series awards must be U.S. citizens, non- citizen nationals, or have been lawfully admitted for permanent residence at the time of award. MECHANISMS OF SUPPORT o Research grant (R01) o Program Project grant (P01) o First Independent Research Support and Transition (FIRST) award (R29) o Career grants, which include: Research Career Development Award (K04); Clinical Investigator Award (K08); Physician Scientist Award (individual K11) o Fellowships (F32, F33) Deadlines for applications are as follows: F-series grants: Jan 10, May 10, Sep 10 New R, K, and P-series: Feb 1, Jun 1, Oct 1 Competing continuation and revised: Mar 1, Jul 1, Nov 1 Foreign institutions are not eligible to apply for Program Project (P01) awards, or FIRST awards (R29). RESEARCH OBJECTIVES The NIA invites researchers to submit applications for research grants, career development awards, and postdoctoral fellowships for studies on the role of DHEA/DHEAS and their metabolic products as they interface with fundamental aging. Of particular interest is the pathway of action and its possible role as a biomarker of aging, including the decline of the immune system and the propensity for increased disease in aging. Of interest also are potential intervention methods to delay and control the aging process with respect to the susceptibility to diseases of the immune, endocrine, and other physiologic systems. Although the interaction of DHEA/DHEAS and their metabolic products and analogs with components of the immune system and various pathophysiologic processes is of primary interest in this Program Announcement, other relevant areas of investigation exploring the communication between the immune and endocrine systems in aging mammals are also of interest and are included within the scope of this Program Announcement. STUDY POPULATIONS 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 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. 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 and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 in Sections 1-4 of the Research Plan AND summarized in Section 3, Recruitment of Individuals from Underrepresented Racial/Ethnic Groups, and 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 must 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. 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 and racial/ethnic minorities 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 review will be deferred until the information is provided. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or 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 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. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) and will be accepted at the standard application deadlines as indicated in the application kit. The receipt dates for applications for AIDS-related research are found in the PHS 398 instructions. National Research Service Award (NRSA) (F32, F33) applications are to be submitted on grant application Form PHS 416 (rev. 10/91). Application kits 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 title and number of this announcement must be typed in Section 2a on the face page of the application. Applications 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. In such a case, a letter of agreement from either the GCRC program director or Principal Investigator could be included with the application. The completed original application and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW PROCEDURES All applications in response to this Program Announcement will be assigned to Initial Review Groups on the basis of the PHS Referral Guidelines and reviewed by the usual Public Health Service Peer Review (Study Section) procedures. They will also be given appropriate primary and secondary Institute assignments in accordance with established PHS Referral Guidelines. The review criteria are the traditional criteria appropriate to each mechanism. In accordance with the standard NIH peer review procedures, research project grant (R01 and R29) applications, fellowships (F32, F33) and research career development awards (K04) will be reviewed for scientific and technical merit by appropriate study sections in the Division of Research Grants. All other applications will be reviewed by review groups of the appropriate Institute. Following the Study Section review, the applications will receive a second-level review by appropriate advisory councils. Funding decisions will be based on the above evaluations and on the availability of funds. AWARD CRITERIA Applications compete for available funds on the basis of scientific merit with other applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program balance among research areas of the announcement INQUIRIES Researchers considering an application in response to this announcement are strongly encouraged to discuss the projects and the range of grant mechanisms available, with NIA staff. This can be done either through a telephone conversation or a brief letter. Applications related to the health of women and minorities are particularly encouraged. Correspondence and inquiries may be directed to: Dr. David Lavrin Immunology Program Administrator Biology of Aging Program National Institute on Aging Gateway Building, Room 2C231 Bethesda, MD 20892 Telephone: (301) 496-6402 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.855. 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 12372 or Health Systems Agency review. .
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