NIH Guide: GENETIC AND MOLECULAR BASIS OF LONGEVITY


GENETIC AND MOLECULAR BASIS OF LONGEVITY

NIH GUIDE, Volume 21, Number 33, September 11, 1992



RFA AVAILABLE:  AG-93-01:



P.T. 34



Keywords:

  Genetics 

  Aging/Gerontology 

  Gene Products 

  Biology, Molecular 

  Biomedical Research, Multidiscipl 



National Institute on Aging



Letter of Intent Receipt Date:  October 1, 1992

Application Receipt Date:  November 13, 1992



THE REQUEST FOR APPLICATIONS (RFA) ANNOUNCED IN THIS NOTICE CONTAINS

ESSENTIAL INFORMATION FOR THE PREPARATION OF AN APPLICATION.  POTENTIAL

APPLICANTS MAY OBTAIN THE RFA FROM THE CONTACT NAMED IN INQUIRIES,

BELOW.



PURPOSE



The National Institute on Aging (NIA) invites applications for R01

grants to support basic research on the genetic and molecular bases of

longevity.  The goals of the Genetic and Molecular Basis of Longevity

RFA are to identify genes that promote longevity and delay the onset of

senescence, termed Longevity Assurance Genes (LAG), and determine the

biochemical functions and molecular mechanisms of action of these LAGs.

A multidisciplinary approach to these complex areas of basic research

will facilitate the application of genetic, biochemical and molecular

techniques to defining the genetic and molecular bases of longevity.



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 RFA,

Genetic and Molecular Basis of Longevity, is related to the priority

area of aging. Delineation of the genetic and molecular bases of

longevity and senescence will lead to a fundamental understanding of

aging processes and hasten the development of biological-based

intervention strategies to extend the human health span. 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 20402-0325, 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, research foundations, hospitals, laboratories, units of State

and local governments, and eligible agencies of the Federal Government.

Applications from domestic institutions may include international

components if the collaborative effort between domestic and foreign

investigators strengthen the research application.  Applications from

minority individuals and women are encouraged.



MECHANISM OF SUPPORT



The multidisciplinary, highly interactive approach outlined in this RFA

is intended to facilitate and enhance research progress toward

understanding complex problems in aging biology.  This RFA is a

one-time solicitation for research applications.  The total project

period for applications submitted in response to this RFA may not

exceed five years.  The anticipated award date for applications

submitted in response to this RFA is July 1, 1993.



The Genetic and Molecular Basis of Longevity research program will be

supported through the traditional research project grant (R01)

mechanism.  Applicants will be responsible for the planning, direction,

and execution of the proposed research projects.  Research applications

from collaborating Principal Investigators at different institutions

are highly encouraged if the combined expertise of the two research

laboratories will facilitate the research progress of both laboratories

and contribute to the overall research goals outlined in this RFA.



FUNDS AVAILABLE



The NIA will set aside a total of $2,000,000 for funding research

projects responsive to the Genetic and Molecular Basis of Longevity RFA

in FY 1993 and expects to make eight to ten grant awards.  Although

this research initiative is provided for in the plans of the NIA, the

award of research grants pursuant to this RFA is contingent upon the

availability of appropriated funds in FY 1993 and the receipt of a

sufficient number of responsive applications with high scientific

merit.



RESEARCH OBJECTIVES



Research with several model systems including yeast, nematodes,

drosophila, rats, mice, and cultured human cells has established that

longevity and senescence are, in part, under genetic control.  The

purposes of this RFA are to stimulate research on the fundamental

mechanisms of aging and senescence, to encourage the application of

results obtained from model systems to understanding human longevity,

and to develop intervention strategies to extend the human health span

based on increased knowledge of fundamental aging mechanisms.  The

interactive, multidisciplinary approach outlined in this RFA is

designed to focus the use of various model systems, human cells and

cell lines, molecular reagents, and state-of-the-art molecular biology

and biotechnology on this important area of aging biology.  The

development of sophisticated methods for molecular cloning, gene

amplification, targeted gene insertion and disruption, and the

production of germ-line transgenic organisms via molecular genetic

manipulation of embryos or embryonic stem cells have made such an

approach feasible.  Application of these powerful molecular approaches

to aging research will facilitate the identification of candidate LAG,

allow evaluation of their effects on longevity and health span in

transgenic model systems, and hasten the search for human homologs of

key LAGs.  It is anticipated that such an approach will facilitate and

optimize research progress and hasten the development of

biological-based intervention strategies designed to prevent or delay

human aging processes and thereby extend the human health span.



The major objectives of the Genetic and Molecular Basis of Longevity

RFA and research initiative are:



o  Development of molecular and animal resources to investigate the

molecular basis of longevity;

o  Identification of candidate LAGs in appropriate models of aging;

o  Evaluation of candidate LAG effects on longevity and senescence in

appropriate transgenic organisms;

o  Characterization of the regulation of LAG expression at the

molecular level;

o  Characterization of the biological functions of proteins encoded by

LAGs, and

o  Identification of human counterparts of key LAGs in cultured cells.



The development and application of several areas of molecular

technology to these problems in aging biology have been identified as

high priority including:



o  Development of suitable expression vectors and protocols for

introduction and stable expression of targeted gene transplacements and

the incorporation of multigenic DNA fragments in mouse embryonic stem

cells.



o  Development of suitable expression vectors and protocols to achieve

cell-specific expression of candidate transgenes in somatic cells of

young adult and aged mice.



o  Identification and characterization of age-specific promoters and

regulatory molecules that could be used to enhance the expression of

candidate genes in aged organisms.



o  Identification of inducible promoters that will drive the expression

of transgenes in aged and senescent animals.



The availability of additional animal models would aid in the

identification and evaluation of candidate LAGs.  For example, the

creation of long-lived strains of mice by selective breeding of highly

outbred founder populations and the genetic and molecular

characterization of these strains is an important aspect of this

research initiative.  In addition, the creation and maintenance of

transgenic mouse lines harboring key LAGs will provide another

important animal resource for this and future research initiatives to

define the genetic and molecular basis of longevity.



Several experimental strategies for the identification and evaluation

of candidate LAGs appear to be appropriate for this RFA.  These include

the evaluation of the effects of known genes believed to have the

characteristics of LAGs (for example, SOD, catalase, and LAG1) on

longevity and health span in transgenic organisms, genetic mapping of

candidate longevity loci in long-lived mouse strains, isolation and

characterization of key genes (regulatory and structural) that are

differentially expressed in animals subjected to caloric restriction

compared to ad libitum fed controls, and identification of human

homologs of LAGs using molecular probes isolated from other model

systems.  In addition, experiments to test the effect of candidate

genes on longevity and senescence in transgenic organisms (invertebrate

and vertebrate) is anticipated via targeted gene disruption and

targeted gene transplacement are encouraged.



The research topics listed above should not be interpreted as the only

experimental approaches to the identification of the genetic and

molecular bases of longevity and senescence. Additional innovative

approaches applicable to the research goals of this RFA are welcome and

encouraged.



SPECIAL REQUIREMENTS



Applicants are responsible for proposing research projects that will

advance the goals of the Genetic and Molecular Bases of Longevity

research initiative.  Applicants must have access to appropriate animal

and/or cell culture models for aging research and have the necessary

expertise in genetics, molecular biology, cell biology, or biochemistry

to carry out the proposed research projects.



LETTER OF INTENT



Prospective applicants are asked to submit a letter of intent by

October 1, 1992.  The letter of intent must include the number and

title of this RFA (AG-93-01), a descriptive title of the proposed

project, and the name, address, phone and FAX numbers of the Principal

Investigator and key co-investigators.  If the application will involve

collaborative or consortium arrangements, the participating

institutions must also be identified.  Although a letter of intent is

not binding and does not enter into the review of the subsequent

application, the letter is requested to provide an indication to the

NIA of the number and scope of applications to be reviewed.



Additional information related to the goals and scope of this RFA will

be provided to investigators who have submitted a letter of intent.

The letter of intent is to be addressed to:



Dr. Anna M. McCormick

Biology of Aging Program

National Institute on Aging

Gateway Building, Suite 2C231

Bethesda, MD  20892

Telephone:  (301) 496-6402

FAX:  (301) 402-0010



APPLICATION PROCEDURES



Applications are due November 13, 1992.  The research grant application

form PHS 398 (rev. 9/91) is to be used in applying for this grant.

These forms are available from most institutional grants and business

offices and from the Office of Grant Inquiries, Division of Research

Grants, National Institutes of Health, Room 449, Westwood Building,

5333 Westbard Avenue, Bethesda, MD  20892-4500.



REVIEW CONSIDERATIONS



Applications judged to be responsive to the RFA and competitive will be

evaluated for scientific and technical merit by an appropriate ad hoc

peer review group convened by the NIA Office of Scientific Review.  The

second level of review, which considers the priorities and special

needs of the NIA, will be conducted by the National Advisory Council on

Aging.



INQUIRIES



The program official welcomes the opportunity to clarify any issues or

questions from potential applicants.  Written and telephone inquiries

concerning the objectives and scope of the Genetic and Molecular Basis

of Longevity RFA, or whether a specific areas of research would be

considered by the NIA as responsive to this RFA are encouraged.



Direct inquires regarding programmatic issues to:



Dr. Anna M. McCormick

Chief, Biology Branch

Biology of Aging Program

National Institute on Aging

Gateway Building, Suite 2C231

Bethesda, MD  20892



Direct inquires regarding fiscal matters to:



Mr. Joseph Ellis

Grants Management Officer

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.  Awards are made under the authorization of the Public

Health Service Act, Title IV, Part A (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

intergovernment review requirements of Executive Order 12372 or Health

Systems Agency review.



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