MOLECULAR AND NEURAL MECHANISMS UNDERLYING THE EFFECTS 0F CALORIC RESTRICTION ON HEALTH & LONGEVITY Release Date: August 22, 2000 RFA: AG-01-002 National Institute on Aging (http://www.nih.gov/nia/) Letter of Intent Receipt Date: September 30, 2000 Application Receipt Date: November 20, 2000 PURPOSE The purpose of this RFA is to solicit applications to conduct research on the mechanisms underlying the effects of caloric restriction (CR) on longevity and health span. Although numerous studies in several species over the past three decades have shown that experimental animals maintained on CR have a longer lifespan than ad libitum controls, the biological process(es) which mediates this effect is unknown. Knowledge about the changes induced by CR at genetic, molecular, cellular, tissue, systems and behavioral levels are needed in order to explore the full range of possible mechanisms. One approach to learning more about the underlying mechanisms takes advantage of the recent advances in genetics with the use of transgenic and knockout animals that target genes affecting longevity, body weight regulation, food intake, metabolism and physical activity. Another approach is to develop and test interventions that mimic the effects that CR induces in experimental animals. HEALTHY PEOPLE 2010 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This Request for Applications (RFA), Molecular and Neural Mechanisms Underlying the Effects of Caloric Restriction on Health & Longevity, is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign for-profit and non-profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. MECHANISM OF SUPPORT This RFA will use the research project grant (R01) mechanism. Responsibility for the planning, direction and execution of the proposed project will be solely that of the applicant/awardee. FUNDS AVAILABLE The NIA intends to commit up to $2,000,000 in FY 2001 to fund new grants in response to this RFA. An applicant may request a project period of up to 5 years. Applicants interested in proposing R01 budgets in excess of $500,000 in direct costs per year should discuss the budget with a program official prior to submission (see Application Procedures). Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the NIA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. At this time, it is not known if the RFA will be reissued. RESEARCH OBJECTIVES It has been known since 1935 that caloric restriction (CR) extends maximum life span in rodents such as rats and mice. More recent results indicate that the development of some age-related pathology is also delayed by CR. Furthermore, CR appears to extend maximum life span in every species in which it has been adequately tested. Trials in rhesus monkeys are currently in progress, but it is too soon to predict whether CR will have an impact on maximum life span in this species, although preliminary results suggest that some changes induced by CR in rodents are mimicked in the CR monkeys. Even if CR can be shown to work in non-human primates, it is unclear whether or not the general population would voluntarily adhere to a similarly restricted nutritional program. Thus, it is imperative to attempt to develop possible mimetic approaches to achieve the same goal. In March 1999, the NIA and NIDDK (National Institute on Diabetes Digestive Diseases and Kidney) co-sponsored the Caloric Restriction Clinical Implications Advisory Group. The Advisory Group reviewed data and made recommendations on epidemiologic, experimental therapeutic, mechanistic, and human intervention studies relating to the relationships of caloric intake, energy balance, and weight gain over the lifespan with longevity and morbidity. The proceedings from this Advisory Group meeting will be published in the Journals of Gerontology: Series A Biological and Medical Sciences, with an anticipated publication date in mid 2000. Notice of publication will be posted on the NIA Website at http://www.nih.gov/nia/news/. Potential applicants interested in conducting research on human aspects of caloric restriction are encouraged to review the companion NIA RFA, (RFA AG-01-001), Sustained Caloric Restriction in Non-Obese Persons: Physiologic Effects and Comparisons/Interactions with Physical Activity . In spite of considerable research on CR funded by the NIA, a mechanism has yet to be established for how CR works. It is known that CR increases resistance to stress and reduces oxidative damage to cellular macromolecules, but causative links have not been established. Although most attention has focused on mitochondrial and other metabolic factors, free radicals and neuronal damage, and physical activity and body composition, less is known about the role(s) played by neuroendocrine/neuropeptide/neurotransmitter systems of the brain. Lowered body weight, in comparison to the body weight of ad libitum fed animals, may be an important component of the life span-enhancing effect of CR. It is well-known that manipulations (e.g., destruction, chemical injection, etc.) of specific regions of the central nervous system (CNS) can result in profound, long-term changes in body weight. For example, destruction of one area of the hypothalamus (ventromedial nucleus) will produce an obese animal, whereas destruction of another area nearby (lateral hypothalamus) can lead to an animal which fails to eat. Thus, there is a strong link between the function of certain CNS areas and the regulation of body weight and food intake. CR could have its effect at several levels: hypothalamus, pituitary, target tissue; and on multiple functions: synthesis, release, action, metabolism as well as target tissue sensitivity (receptor function). There are both species and strain differences (rats and mice have been studied), and few studies have been able to assess the entire life span. CR effects may differ when the manipulation is chronic vs. acute, in males vs. females, when CR is initiated at different ages or at different stages of reproduction in the case of females. In addition, the percentage of ad libitum intake used for CR is not consistent among studies. The type of feeding schedules may influence the release of critical hormones, peptides or transmitters; receiving one large meal per day could have different metabolic consequences from receiving several smaller meals that are spaced to more closely simulate the animal’s natural feeding rhythm. Thus, these variables with regard to CR and CNS function require further investigation. The major objectives of this RFA include, but are not limited to, applications designed to address one or more of the following in mammalian and/or non-mammalian systems (including unicellular organisms): o Identification of the critical metabolic changes associated with CR o Investigation of which of the many changes (metabolic and/or non- metabolic) induced by CR are critical to life span extension o Understanding of the role played by reduction of oxidative stress in life span extension by CR o Investigation of the role played by reduction of blood glucose levels in life span extension by CR o Development of mimetics which induce life span extension in the absence of dietary restriction o Elucidation of the neuroendocrine, neuropeptide and neurotransmitter changes induced by CR o Use of genetically altered mice to mimic changes induced by CR o Characterization of age-related changes that are affected by CR by use of high throughput technology such as microarrays o Studies of the association between CR and changes in responsiveness to sensory characteristics such as taste and smell o Studies of longevity and body weight regulation in transgenic and knockout animal models in which the manipulated gene has been shown to influence food intake, metabolism or physical activity o Studies of changes in sensitivity of CR animals to pharmacological agents known to have short- or long-term effect on food intake, body weight control, physical activity or metabolism o Investigation of cognitive changes in CR animals and in genetically- manipulated animals with modified lifespan SPECIAL REQUIREMENTS Applicants should state their willingness to participate in one-day annual meetings to track the progress of their studies and to promote exchange of experiences and ideas. Attendees to these meetings will include the grantees funded under this RFA as well as grantees funded under the companion NIA RFA Sustained Caloric Restriction in Non-Obese Persons: Physiologic Effects and Comparisons/Interactions with Physical Activity (RFA AG-01-001) as an exchange of data and ideas between researchers conducting basic/molecular studies and clinical research on the effects of caloric restriction will be invaluable in guiding future studies in this area. Funds for travel to the Washington D.C. area for the Principal Investigator (and up to two co-investigators, if appropriate) should be included in the budget for each year. INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are provided indicating 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). All investigators proposing research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html); a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_update.htm: The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to provide a description of plans to conduct analyses, as appropriate, to address differences by sex/gender and/or racial/ethnic groups, including subgroups if applicable; and b) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. URLS IN NIH GRANT APPLICATIONS OR APPENDICES All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to one of the program staff listed under INQUIRIES by the letter of intent receipt date listed in the heading of this RFA. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research; 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: grantsinfo@nih.gov; and on the internet at: http://grants.nih.gov/grants/forms.htm The RFA label found in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The sample RFA label at http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. Submit a signed original of the application, including the Checklist, and three signed photocopies of the application in one package 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 copies of the application to: Mary Nekola, Ph.D. Chief, Scientific Review Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Room 2C212 Bethesda, MD 20892-9205 It is important to send these copies at the same time as the original and three copies are sent to the Center for Scientific Review. These copies are used to identify conflicts and to help ensure the appropriate and timely review of the application. Applications must be received by the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (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 responsiveness by NIA. Incomplete applications will be returned to the applicant. 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 the RFA will be evaluated for scientific and technical merit by an appropriate peer review group convened by 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. Review Criteria The goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the 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 these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. 1. Significance: Does the study address an important problem related to the research objectives of this RFA? If the aims of the application 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? 2. 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? 3. Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? 4. 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)? 5. 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: o 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. o The reasonableness of the proposed budget and duration in relation to the proposed research. o 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. The personnel category will be reviewed for appropriate staffing based on the requested percent effort. The direct costs budget request will be reviewed for consistency with the proposed methods and specific aims. The duration of support will be reviewed to determine if it is appropriate to ensure successful completion of the requested scope of the project. Schedule: Letter of Intent Receipt Date: September 30, 2000 Application Receipt Date: November 20, 2000 Date of Initial Review: February 2001 Review by Advisory Council: May 2001 Anticipated Award Date: July 1, 2001 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit as determined by peer review o Availability of funds o Balance among the projects in addressing different experimental approaches and their complementarity to other ongoing efforts o Extent to which the proposed research supports the goals of the NIA INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: David B. Finkelstein, Ph.D. Biology of Aging Program National Institute on Aging Gateway Building, Suite 2C231 Bethesda, MD 20892 TEL: 301/496-6402 FAX: 301/402-0010 Email: FinkelsD@exmur.nia.nih.gov or Judith A. Finkelstein, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Building, Suite 3C307 Bethesda, MD 20892 TEL: 301/496-9350 FAX: 301/496-1494 Email: FinkelsJ@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 2N212 Bethesda, MD 20892 TEL: 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 authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract 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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