NIH GUIDE, Volume 23, Number 28, July 29, 1994

PA NUMBER:  PA-94-087

P.T. 34




National Institute on Aging

National Institute of Diabetes and Digestive and Kidney Diseases


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.


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).


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.


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 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.



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


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,


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.


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


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**


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.


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


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


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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