GENETIC AND MOLECULAR BASIS OF LONGEVITY

Release Date: March 26, 1998 

RFA:  AG-98-005

P.T.

National Institute on Aging

Letter of Intent Receipt Date:  May 1, 1998
Application Receipt Date:  June 10, 1998

PURPOSE

The National Institute on Aging (NIA) invites applications for new and competing
renewal applications for research project grants (R01) to support basic research
on the genetic and molecular basis of longevity.  The goals of the Genetic and
Molecular Basis of Longevity Request for Applications (RFA) are to identify genes
that play a role in determining longevity and health span and to determine the
cellular and biochemical functions, and molecular mechanisms of action of these
Longevity Assurance Genes (LAGs).  Longevity Assurance Genes are operationally
defined as genes that: determine or promote longevity and extend health span,
maintain cell, tissue and/or organ function and organismal homeostasis. Candidate
genes that fit one or more of these classifications have been identified in
invertebrates, mammals and humans.  A multidisciplinary approach to the study of
the complex traits of longevity and aging, including the application of genetic,
molecular, and biochemical techniques, has accelerated research progress toward
an in depth understanding of the molecular genetic basis of longevity and aging. 
The continued application of multidisciplinary approaches to the investigation
of these areas of aging biology is strongly recommended in applications submitted
in response to this RFA.

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. Each NIH RFA addresses one or more of 22
Health Promotion and Disease Prevention priority areas identified.  These areas
can be found via the WWW at http://www.crisny.org/health/us/health7.html.

ELIGIBILITY REQUIREMENTS

Applications may be submitted by domestic and foreign, non-profit and for-profit
organizations, public and private, such as universities, colleges, research
foundations, hospitals, and 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 efforts
between domestic and foreign investigators strengthen the research proposal. 
Applications from women and minority individuals are encouraged.

MECHANISM OF SUPPORT

This RFA continues an NIA research initiative begun in 1993. New and competing
renewal applications for R01 research project grants are encouraged.  Applicants
will be responsible for the planning, direction, and execution of the proposed
research projects. All applicants are encouraged to specify how the proposed
research will further the objectives of this RFA.

New applications will compete on an equal basis with competing renewals. The
total project period for all applications submitted in response to this RFA must
be five years. The earliest anticipated award date for successful grant
applications is February 1, 1999.  Depending on progress, and NIA priorities and
budget, an RFA may be issued to continue this research initiative at the end of
the five-year cycle.

FUNDS AVAILABLE

The NIA will set aside a total of $4 million dollars in FY 1999 to fund
meritorious research projects responsive to the Genetic and Molecular Basis of
Longevity RFA and expects to make about fifteen 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 funds
and the receipt of a sufficient number of responsive applications with high
scientific merit.

RESEARCH OBJECTIVES

Research in several experimental models of longevity and aging including yeast,
nematodes, fruit flies, mice, rats, and human cells has clearly established that
aging and longevity are, in part, under genetic control.  Identification and
functional characterization of specific genes or gene subsets that play a role
in determining longevity or health span, and/or significantly contribute to one
or more aging processes are central to understanding the fundamental genetic and
molecular mechanisms that govern longevity and aging.  The scientific objectives
of this RFA are: 1) to stimulate research on the fundamental mechanisms that
determine longevity in several species (ranging from invertebrates to humans; 2)
to encourage the application of research advances obtained in animal models to
understanding human longevity and aging; and 3) to develop and test experimental
intervention strategies that promote longevity and extend health span.  The
multidisciplinary, interactive research approach outlined in this RFA is designed
to integrate the genetic, molecular and biochemical analysis of various animal
and human models of longevity and aging with state-of-the-art biotechnology in
a concerted effort to understand the fundamental mechanisms which contribute to
longevity and aging.  Enhanced knowledge of these fundamental mechanisms will
guide and hasten the development of effective prevention and intervention
strategies to promote human longevity and extend health span.

Several genes involved in determining longevity and/or extending health span have
recently been identified in Saccharomyces  cerevisiae, Caenorhabditis elegans,
Drosophila melanogaster,  Mus musculus, and humans.  In addition, caloric
restriction (total calorie reduction without malnutrition) has been shown to
increase longevity and extend health span in short-lived mammals (mice/rats). 
Although more complex than the invertebrate models of longevity and aging, ad
libitum fed and calorically-restricted rodents also provide excellent and
under-utilized model systems for the identification of candidate mammalian LAGs.

Recent technological developments including sophisticated methods for
identification of differentially expressed genes, targeted gene knockout and
transgene insertion, and conditional gene expression in transgenic organisms
should facilitate the identification and functional characterization of candidate
LAGs and their human homologs and orthologs.

The major research objectives of the Genetic and Molecular Basis of Longevity
Initiative and RFA are:

o  Development of biological resources (animal and cell models) and molecular
reagents to investigate the genetic and molecular basis of longevity/aging

o  Development and evaluation of conditional gene expression vectors/systems
capable of achieving age-specific and/or tissue-specific LAG expression in
cultured cells and/or aged transgenic organisms

o  Identification of candidate LAGs in animal or human models

o  Identification of single nucleotide polymorphisms or other allelic variations
in candidate LAGs

o  Identification of human homologs and orthologs of invertebrate and mammalian
LAGs

o  Evaluation of candidate LAG effects on longevity, aging and senescence in
transgenic cells and/or organisms

o  Characterization of the biological and physiological functions of proteins
encoded by candidate LAGs

o  Characterization of the molecular mechanisms controlling temporal and cellular
regulation of LAG expression

This RFA does not extend to research on the effects of known polymorphisms on
longevity in human populations.

Appropriate models for the identification of candidate LAGs include, but are not
limited to:

o  the yeast Saccharomyces cerevisiae

o  short- and long-lived strains of the nematode Caenorhabditis elegans including
daf, age and other appropriate mutants

o  short- and long-lived strains of Drosophila melanogaster and recombinant
inbred lines created from crosses of the short- and long-lived lines

o  short- and long-lived lines of mice, including mutant strains and selectively
bred genetically heterogeneous mice

o  mice fed ad libitum or calorically restricted diets

o  transgenic nematodes, flies or mice bearing either ubiquitously or
conditionally expressed candidate LAGs

o  human cells and cell lines.

SPECIAL REQUIREMENTS

Applicants are responsible for proposing research projects that will advance the
goals of the Genetic and Molecular Basis of Longevity Research Initiative. 
Principal and collaborating investigators must demonstrate their access to the
animal models, cell culture models, and/or appropriate human cells required for
completion of the proposed research.

Investigators conducting biomedical research frequently develop unique research
resources.  The policy of the PHS is to make available to the public the results
and accomplishments of the activities that it funds. All applications must adhere
to PHS policy for the distribution of unique research resources produced with PHS
funding published in the NIH Guide for Grants and Contracts (NIH Guide, Vol. 25,
No. 23, July 12, 1996) which may be found on the internet at:
http://grants.nih.gov/grants/guide/notice-files/not96-184.html.

Investigators are encouraged to develop and apply interactive strategies,
particularly the establishment of collaborative teams, to the identification and
functional characterization of candidate LAGs and the search for human homologs
and orthologs of candidate LAGs identified in invertebrate and mammalian model
systems in applications submitted in response to this RFA. Collaborative R01
applications from Principal Investigators at different Institutions are strongly
encouraged if the combined expertise of the collaborating research laboratories
will facilitate the research progress of both laboratories and contribute to a
fundamental understanding of the genetic and molecular basis of longevity. 
Applicants may request funds to facilitate the logistics of collaborative studies
related to the proposed research. Collaborative R01 grants may be from a single
institution or several institutions, may include shared resources, and must
demonstrate the interdependence of the individual components of the collaborative
R01. Such requests may include funds for shared resources or equipment,
inter-laboratory communication strategies, travel funds, or other mechanisms to
enhance collaborative interactions among investigators.  Justifications for funds
requested to facilitate collaborative interactions should be included in the
Budget Justification section of the application.

Applications funded from this RFA will be incorporated into the NIA Longevity
Assurance Gene Interactive Network composed of NIA-supported investigators
involved in research to define the genetic and molecular basis and mechanisms of
longevity and aging.  Annual meetings of the LAG Interactive Network Principal
Investigators and NIA program officials will be held to promote scientific
exchange and resource sharing.  Travel funds ($2,000 per year) for Principal
Investigators to attend annual LAG Interactive Network Meetings (1-2 per year)
should be included in the requested travel budgets. The LAG Interactive Network
meetings will be coordinated by NIA Program officials to establish research
priorities, review research progress and experimental difficulties, coordinate
resource and data sharing, and discuss new technological developments applicable
to this research program.

INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS

It is the policy of 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
policy results from the NIH Revitalization Act of 1993 (Section 492B of Public
Law 103-43) and supersedes and strengthens the previous 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 28, 1994 (FR
59 14508-14513) and in the NIH Guide for Grants and Contracts, Volume 23, Number
11, March 18, 1994.

Investigators may also obtain copies of the policy from the program staff listed
under INQUIRIES.  Program staff may also provide additional relevant information
concerning the policy.

LETTER OF INTENT

Prospective applicants are asked to submit, by May 1, 1998, a letter of intent
that includes a descriptive title of the proposed research project, the name,
address, Email address, and telephone number of the Principal Investigator,
collaborating investigators, and other key personnel, and the number and title
of the RFA in response to which the application may be submitted.  If the
application will involve collaborative or consortium arrangements, the
participating institutions must also be identified.  Although a letter of intent
is not required, is not binding, and does not enter into the review of the
subsequent application, the information that it contains allows NIA staff to
estimate the potential review workload and avoid conflict of interest in the
review.

The letter of intent is to be sent (mail, FAX, Email versions are acceptable) to:

Anna M. McCormick, Ph.D.
Biology of Aging Program
National Institute on Aging
Gateway Building, Suite 2C231
Bethesda, MD  20892
FAX:  (301) 402-0010
Email:  mccormia@exmur.nia.nih.gov

APPLICATION PROCEDURES

The research grant application form PHS 398 (rev. 5/95) is to be used in applying
for these grants.  Application kits are available at most institutional offices
of sponsored research and may also be obtained from the Division of Extramural
Outreach and Information Resources, National Institutes of Health, 6701 Rockledge
Drive, MSC 7910, Bethesda, MD 20892-7910, telephone: 301-435-0714, Email:
ASKNIH@od.nih.gov. Applications are also available on the World Wide Web at
http://grants.nih.gov/grants/funding/phs398/phs398.html.

The RFA label provided in the PHS 398 application packet must be affixed to the
bottom of the face page.  Failure to use the RFA label could result in delayed
processing of the application such that it may not reach the assigned review
committee in time for review. In addition, the RFA title (Genetic and Molecular
Basis of Longevity) and number (AG-98-005) must be typed on line 2 of the face
page of the application form and the YES box must be marked.

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

CENTER FOR SCIENTIFIC REVIEW
NATIONAL INSTITUTES OF HEALTH
6701 ROCKLEDGE DRIVE, ROOM 1040-MSC 7710
BETHESDA, MD  20892-7710
BETHESDA, MD  20817 (for express/courier service)

At the time of submission, send two additional photocopies of the application to:

Dr. Mary Nekola
Scientific Review Office
National Institute on Aging
Gateway Building, Suite 2C212
Bethesda, MD  20892
Bethesda, MD  20814 (for express/courier service)

Complete applications must be received by the Center for Scientific Review (CSR),
NIH by June 10, 1998 and must satisfy all the requirements of the RFA.  If the
application is received after that date, it will be returned to the applicant
without review.  The CSR will not accept any application in response to this RFA
that is essentially the same as one currently pending initial review, unless the
applicant withdraws the pending application.  The CSR 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 for completeness by CSR and for
responsiveness by the NIA. If the application is not responsive to the RFA, CSR
staff may contact the applicant to determine whether to return the application
to the applicant or submit it for review in competition with unsolicited
applications at the next review cycle.  Applications that are complete and
responsive to this RFA will be evaluated for scientific and technical merit by
an appropriate peer review group convened by the NIA in accordance with the
review criteria stated below.  As part of the initial merit review, all
applications will receive a written critique and may undergo a process in which
only those applications deemed to have the highest scientific merit, generally
the top half of applications under review, will be discussed, assigned a priority
score, and receive a second level review by the National Advisory Council on
Aging.

The goals of NIH-supported research are to advance our understanding of
biological systems, improve the control of disease, and enhance health.  In their
written comments, reviewers will be asked to discuss the following aspects of the
application in order to judge the likelihood that the proposed research will have
a substantial impact on the pursuit of these goals.  Each of the criteria will
be addressed and considered in assigning the overall score, weighting them as
appropriate for each application.

* Significance:  Does this study address an important problem?  If the aims of
the applications are achieved, how will scientific knowledge be advanced?  What
will be the effect of these studies on the concepts or methods that drive this
field?

* Approach:  Are the conceptual framework, design, methods, and analyses
adequately developed, well-integrated, and appropriate to the aims of the
project?  Does the applicant acknowledge potential problem areas and consider
alternative tactics?

* Innovation:  Does the project employ novel concepts, approaches, or methods? 
Are the aims original and innovative?  Does the project challenge existing
paradigms or develop new methodologies or technologies?

* Investigator:  Is the investigator appropriately trained and well suited to
carry out this work?  Is the work proposed appropriate to the experience level
of the principal investigator and other researchers (if any)?

* Environment:  Does the scientific environment in which the work will be done
contribute to the probability of success?  Do the proposed experiments take
advantage of unique features of the scientific environment or employ useful
collaborative arrangements?  Is there evidence of institutional support?

In addition to the above criteria, in accordance with NIH policy, all
applications will also be reviewed with respect to the following:

* The reasonableness of the proposed budget and duration in relation to the
proposed research.

* The adequacy of plans to include both genders, minorities, and their subgroups
as appropriate for the scientific goals of the research. Plans for the
recruitment and retention of subjects will also be evaluated.

* The adequacy of the proposed protection for humans, animals or the environment,
to the extent they may be adversely affected by the project proposed in the
application.

* Availability of special opportunities for furthering research programs through
the use of unusual talent resources, populations, or environmental conditions in
other countries which are not readily available in the United States, or which
provide augmentation of existing U.S. resources (for foreign applications only).

The application of creative and innovative (high risk/high impact) experimental
approaches and the development of interactive strategies and collaborative teams
to the research goals of this RFA are encouraged.

AWARD CRITERIA

Applications will compete for available funds with all other approved
applications submitted in response to this RFA.  The following criteria will be
considered in making funding decisions:

* Scientific and technical merit of the proposed project as determined by peer
review

* Program priority and balance

* Availability of funds

* Adequacy of plans for distribution of unique research resources

INQUIRIES

Written, telephone, and email inquiries concerning the objectives and scope of
this RFA and questions as to whether specific areas of research would be
considered responsive to this RFA are encouraged.  The opportunity to clarify any
issues or questions from potential applicants is welcome.

Direct inquiries regarding programmatic issues 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
Email:  mccormia@exmur.nia.nih.gov

Direct inquiries regarding scientific review to:

Dr. Mary Nekola
Scientific Review
National Institute on Aging
Gateway Building, Suite 2C212
Bethesda, MD  20892
Telephone:  (301) 496-9666
FAX:  (301) 402-0066
Email:  nekolam@exmur.nia.nih.gov

Direct inquiries regarding fiscal matters to:

Mr. Joseph Ellis
Grants and Contracts Management Office
National Institute on Aging
Gateway Building, Suite 3N212
Bethesda, MD  20892
Telephone:  (301) 496-1472
FAX:  (301) 402-3672
Email:  ellisj@exmur.nia.nih.gov

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 inter-government review requirements of
Executive Order 12372 or Health Systems Agency Review.

The Public Health Service (PHS) strongly encourages all grant recipients to
provide a smoke-free workplace and promote the non-use of all tobacco products.
In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking
in certain facilities (or in some cases, any portion of a facility) in which
regular or routine education, library, day care, health care or early childhood
development services are provided to children.  This is consistent with the PHS
mission to protect and advance the physical and mental health of the American
people.


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