Full Text AG-93-01

GENETIC AND MOLECULAR BASIS OF LONGEVITY

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

RFA:  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

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
Request for Applications (RFA) are to identify genes which promote
longevity and delay the onset of senescence, termed Longevity Assurance
Genes (LAGs), 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 proposal. 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.  Should the NIA
determine that there is sufficient need to continue this research
program, the NIA may announce a request for new competitive and/or
competitive renewal applications related to the Genetic and Molecular
Basis of Longevity in the form of a second RFA.

FUNDS AVAILABLE

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.

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.
Identification and characterization of the specific genes that
determine longevity and contribute to aging and senescence in several
species including humans are central to understanding the fundamental
molecular mechanisms that govern aging and senescence.  Moreover,
knowledge of these fundamental mechanisms will guide and hasten the
development of effective prevention and intervention strategies to
extend the human health span.

The only experimental paradigm known to significantly extend the life
span and health span of mammals (mice and rats) is caloric restriction.
The molecular mechanisms responsible for the increased longevity and
postponed senescence in these short-lived mammals are poorly
understood.  Although more complex than the invertebrate models of
aging and senescence, ad libitum fed and calorically restricted rodents
provide excellent models to begin the search for candidate mammalian
LAGs.

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 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 LAGs,
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 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.

Appropriate models for the identification of candidate LAGs include:

o  The yeast Saccharomyces cerevisiae;

o  Short- and long-lived strains of the nematode Caenorhabditis elegans
including age mutants;

o  Short- and long-lived strains of Drosophila melanogaster;

o  Short-lived and longer-lived species of mice including Peromyscus;

o  Mice fed ad libitum or calorically restricted diets;

o  Long-lived strains of mice created by selective breeding of
genetically heterogenous founder populations;

o  Transgenic mice bearing candidate LAGs or putative longevity loci;

o  Human cell lines which display differentiated functions and
senescence in vitro; and

o  Mice created from embryonic stem cells selected in vitro for
particular traits or adaptive responses predicted to have potentially
significant effects on longevity and senescence (e.g., enhanced
resistance to oxidative damage, heat shock and other forms of
biological stress).

Investigators wishing to evaluate the effects of candidate LAGs on
mammalian longevity and senescence are encouraged to apply
state-of-the-art transgenic mouse technology, including the use of
homologous recombination for targeted gene transplacement and gene
disruption, to the construction of appropriate transgenic lines of
mice.  Investigators are encouraged to include strategies, including
the establishment of collaborative arrangements, for the identification
and characterization of human homologs or equivalents of candidate LAGs
identified in yeast, invertebrates and mammalian model systems in
applications submitted in response to this RFA.

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 which could be used to enhance the expression of
candidate genes in aged organisms; and

o  Identification of inducible promoters which 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) which 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 to be 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.

Investigators supported by the Genetic and Molecular Basis of Longevity
Initiative will interact with each other and the NIA Biology of Aging
Program Staff on a regular basis.  The initial meeting of grant
awardees and Biology of Aging Program staff will serve to coordinate
the individual research projects and Principal Investigators (PIs).
Yearly workshops in which grantees and NIA program staff will
participate will be arranged to establish research priorities, review
research progress and experimental difficulties, coordinate ongoing
research, plan future research activities, and discuss new developments
in molecular biology and biotechnology applicable to this research
program.  Travel funds to attend the yearly workshops in the amount of
$2,000 per year are to be included as a line item in each project
budget.

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 PI and key
personnel. 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 FAX

APPLICATION PROCEDURES

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.

The title of this RFA, Genetic and Molecular Basis of Longevity, and
the RFA number, AG-93-001, must be typed on line 2a of the face page of
the application form to ensure that it is assigned to the NIA upon
receipt by the Division of Research Grants.  The RFA label available in
the application form PHS 398 must be affixed to the bottom of the face
page. Failure to use this label could result in delayed processing of
your application such that it does not reach the review committee in
time for review. The page limitation guidelines outlined in the PHS 398
application packet apply to all applications submitted in response to
this RFA.

Submit the signed original of the application, including the Checklist,
and three signed exact photocopies (single-sided) in one package to:

Division of Research Grants
Westwood Building, Room 240
5333 Westbard Building
Bethesda, MD  20892-4500

In addition, one copy must be sent to the NIA Program Official and one
copy must be sent to the NIA Scientific Review Office.  The appropriate
addresses for these individuals are:

Dr. Anna M. McCormick
Chief, Biology Branch
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892

Dr. Michael Oxman
Chief, Scientific Review Office
National Institute on Aging
Gateway Building, Suite 2C212
Bethesda, MD  20892

Complete applications are due November 13, 1992, and must address all
requirements in the RFA.  Applicants are advised to obtain the
necessary institutional approval for the use of vertebrate animals and
human tissues, as appropriate, prior to the submission of an
application.  Applications received after the receipt date will be
returned to the applicant without review.  The Division of Research
Grants (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.

REVIEW CONSIDERATIONS

Upon receipt, applications will be reviewed by DRG staff for
completeness.  Incomplete applications will be returned to the
applicant without further consideration. Applications judged to be
non-responsive to this RFA will be returned, but may be resubmitted as
investigator-initiated research grant applications at the next
application receipt date. Applications may first receive a preliminary
review by a subcommittee of the review panel to establish those
applications deemed to be competitive.  The NIH will withdraw from
further consideration those applications judged to be noncompetitive
and will notify the applicant PI and the institutional official of this
action. Applications judged to be responsive 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, by the National Advisory Council on Aging,
considers the priorities and special needs of the NIA.

Reviewers will be asked to review the applications considering the
following criteria:  scientific merit, feasibility and relevance of the
proposed project to the overall goals and objectives of the RFA;
proposed techniques and methodologies to achieve the stated research
goals; qualifications, expertise and proposed responsibilities of the
PI and key personnel; scientific plans and timetable for implementing
the proposed research program; and facilities, resources, and
environment available to the PI and co-investigators.  The initial
review group will critically examine the submitted budget and will
recommend an appropriate budget and period of support for each
application.

INQUIRIES

The Program and Grants Management officials welcome the opportunity to
clarify any issues or questions from potential applicants.  Written and
telephone inquiries concerning the objectives and scope of this RFA and
questions as to 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
Telephone:  (301) 496-6402
FAX:  (301) 402-0010

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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