NEUROENDOCRINOLOGY OF AGING NIH GUIDE, Volume 23, Number 28, July 29, 1994 PA NUMBER: PA-94-087 P.T. 34 Keywords: Aging/Gerontology Neuroendocrinology National Institute on Aging National Institute of Diabetes and Digestive and Kidney Diseases PURPOSE The National Institute on Aging (NIA) and the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) announce an ongoing interest in supporting basic and clinical research addressing aging of neuroendocrine systems and their sequelae. Mechanistic approaches at either the organismic, cellular, or molecular levels are encouraged. 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 Program Announcement, Neuroendocrinology of Aging, is related to the priority area of aging and the increasing years of healthy productive life. 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 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. Foreign institutions are eligible for First Independent Research Support and Transition (FIRST) (R29) awards. Applications from minority individuals and women are encouraged. MECHANISM OF SUPPORT Awards will be administered under PHS grants policy as stated in the PHS Grants Policy Statement, DHHS Publication No. (OASH) 94-50,000 (rev. 4/1/94). Research will be supported by research project grants (R01) and FIRST awards (R29). RESEARCH OBJECTIVES Background Research accumulated over the past decade has solidified the view that changes in neuroendocrine control systems underlie the wide range of impaired body functions normally associated with advanced chronological age. The major challenge that now faces investigators in the field is to understand more clearly how deficits in brain-pituitary function arise with age, and the relationship of these deficits to imbalances in peripheral organ system homeostatic control. The maintenance of homeostasis in the face of environmental stress is largely under the control of the neuroendocrine system. With age, there appears to be a decreased capacity to adapt to changes in the environment. Frequently, the response is delayed and of lower magnitude in the older individual. These responses are mediated primarily through the neuroendocrine system. Thus, it is important to identify and elucidate the mechanisms underlying age-related changes in the neuroendocrine system, and conversely, to understand and to characterize how the endocrine system impinges upon and controls the nervous system. For example, circadian and other biological rhythms are central to these homeostatic processes. At least some of these rhythms are coupled to circadian fluctuations in the secretion of aminergic and peptidergic neurotransmitters as well as pituitary hormones. Blended on top of these daily rhythms in hormone release are more frequent ultradian fluctuations. To date, few data exist that examine the relationship between circadian rhythms and the shorter ultradian rhythms. Such information is critical since disruption of the central timing mechanism governing circadian rhythms such as sleeping and eating as seen in older individuals could underlie a cascade of age-associated changes in neuroendocrine function, and in particular, pulsatile hormone release, which could compromise processes involved in growth, metabolism, and reproduction. The NIA also continues to encourage research leading to a better understanding of the menopause and its sequelae. It has long been thought that menopause, or the cessation of regular reproductive cycles, is due to the exhaustion of ovarian follicles with aging. More recently, it has become clear that the decline in reproductive function that occurs in aging may also be due to age-related disruption of the biological clock, which results in altered secretion and secretory patterns of neurotransmitters and hormones and altered gene expression in cells producing these substances. Thus, research focusing on the identification and elucidation of the mechanisms underlying the neuroendocrine etiologies of menopause are encouraged. It has been proposed that age-related degeneration in certain central nervous system (CNS) tissues can be related, in part, to the neurotoxic effect caused by their repeated exposure to circulating steroids. This has been most evident in the relationships between corticosteroids and estrogens to hippocampal and hypothalamic degeneration, respectively. Additional research is needed to further explore and delineate the processes potentially responsible for these neurodegenerative disorders associated with aging. Estrogen receptor mRNA has been demonstrated to be distributed in the adult rat brain not only in regions that are known targets of estrogen, such as the hippocampus and the hypothalamic preoptic nuclei, but also in regions not typically considered as targets for estrogen action such as the basal forebrain. Recent findings indicate that estrogen receptors colocalize with neurotrophin receptors in cholinergic neurons within the basal nucleus of Meynert, suggesting that estrogen may modulate the functioning of these cells that form part of the neural substrate of cognition. Colocalization of estrogen and nerve growth factor receptors also have been found in the dorsal root ganglia of adult female rats; the expression of both classes of receptors were regulated by estrogen, supporting the hypothesis that estrogen may play a functional role in the regulation of neuronal responsiveness to neurotrophins. Further research is required to elucidate these estrogen-neurotrophin interactions. Furthermore, it is becoming more evident that cytokines produced by various immune tissues may affect the neuroendocrine axis. These cytokines can be released either into the bloodstream or in the local vicinity of nervous tissue to exert their actions. This bidirectional communication between the immune and endocrine systems is paramount to homeostatic control. Noting the well-documented decline in the function of both these systems with age, it would seem that senescence could alter the precise balance in immune-endocrine communication. Consequently, research is encouraged to examine potential consequences of the aging immune and endocrine systems and their interactions on neuroendocrine function. The NIDDK has long been interested in understanding the interrelationships between the hypothalamic-pituitary-adrenal/gonadal axes and the immune system in response to stress and disease. The NIDDK is acutely aware of the role(s) played by external sensory inputs, related through these axes, on circadian and ultradian cycles of hormonal and behavioral regulation. The NIDDK also continues to foster research on the roles of both members of the steroid/thyroid/ retinoid supergene family and growth factors on brain function. To help identify opportunities for further research in this area, the NIA convened a workshop on the Neuroendocrinology of Aging: Perspectives and Prospectives. The proceedings of this meeting have been published in Neurobiology of Aging, 15(4), 1994 Specific Goals and Scope To address the general objectives discussed above, NIA and NIDDK encourage submission of applications for research relating to the neuroendocrinology of aging that address one or more of the following areas, which are illustrative and are not intended to be restrictive. o Investigations of the molecular and cellular processes modulating the aging hypothalamic neuroendocrine system, as well as the mechanisms causing neuroendocrine decline with age. o Elucidation of the mechanisms underlying the loss of, or alterations in, neuroendocrine rhythms with age. o Studies of how the aging circadian system acts upon ultradian hormone rhythms (e.g., pulsatile hormone release). o Identification of the effects of systemic steroids (e.g., glucocorticoids, estrogens) on cytoarchitecture and synaptic organization and remodeling, and the elucidation of the mechanisms of action of hormones on neural cells. o Evaluation of steroid antagonists or agonists as a means to mitigate or delay potential neurotoxic consequences of steroid exposure. o Investigation of CNS mechanisms that may alter the rate of reproductive senescence. o Studies of how networks of organ systems that share signal molecules, such as the endocrine, immune, and nervous systems, mutually regulate their complex interactions, and whether alterations in these interactions result in impaired neural homeostatic controls leading to increased likelihood of pathologies and disease. o Determination of the mechanisms controlling the effects of dietary restriction on the neuroendocrine system. o Identification of the roles and underlying mechanisms played by the hypothalamic neuroendocrine system in the aging process, and establishment of whether neuroendocrine interventions can inhibit or reverse the aging process. STUDY POPULATIONS INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the National Institutes of Health (NIH) that women and members of minority groups and their subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This new policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43) and supersedes and strengthens the previous policies (Concerning the Inclusion of Women in Study Populations, and Concerning the Inclusion of Minorities in Study Populations), which have been in effect since 1990. The new policy contains some provisions that are substantially different from the 1990 policies. All investigators proposing research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which have been published in the Federal Register of March 9, 1994 (FR 59 11146-11151) and reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. Application kits are available at most institutional offices of sponsored research and may be obtained from the Office of Grants Information, Division of Research Grants, National Institutes of Health, Westwood Building, Room 449, Bethesda, MD 20892, telephone 301/710-0267. The title and number of this program announcement must be typed in Section 2a on the face page of the application. Applications for the FIRST Award (R29) must include at least three sealed letters of reference attached to the face page of the original application. FIRST Award (R29) applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. 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. 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 CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be reviewed for scientific and technical merit in accordance with the standard NIH peer review procedures. Following scientific-technical review, the applications will receive a second-level review by an appropriate National Advisory Council. The following criteria will be used in evaluating applications submitted in response to this program announcement: o Scientific and technical merit, significance, and originality of the proposed research; o Appropriateness and adequacy of the experimental approach and methodology to be used; o Qualifications of the principal investigator and staff in the area of research, and the principal investigator's prior research experience and record; o Adequacy of the available facilities. AWARD CRITERIA Applications will compete for available funds with all other approved applications assigned to that Institute, Center, or Division. 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 Written and telephone inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Andrew A. Monjan, Ph.D., M.P.H. Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Building, Suite 3C307 Bethesda, MD 20892 Telephone: (301) 496-9350 FAX: (301) 496-1494 Phillip Smith, Ph.D. Endocrine and Metabolic Diseases Program Branch National Institute of Diabetes and Digestive and Kidney Diseases Westwood Building, Room 621 Bethesda, MD 20892 Telephone: (301) 594-7531 FAX: (301) 594-9011 Direct inquiries regarding fiscal matters to: Vicki Maurer Grants and Contracts Management Office National Institute on Aging Gateway Building, Suite 2N212 Bethesda, MD 20892 Telephone: (301) 496 1472 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.866, Aging 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 12372 or Health Systems Agency review. .
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