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. .