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: https://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: 301-710-0267, Email: ASKNIH@od.nih.gov. Applications are also available on the World Wide Web at https://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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