RFA-AG-02-002: CALORIC RESTRICTION AND AGING IN NIA NON-HUMAN PRIMATES

Department of Health
and Human Services (HHS)

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CALORIC RESTRICTION AND AGING IN NIA NON-HUMAN PRIMATES Release Date: June 18, 2001 RFA: RFA-AG-02-002 National Institute on Aging (http://www.nih.gov/nia/) Letter of Intent Receipt Date: November 11, 2001 Application Receipt Date: December 11, 2001 PURPOSE The purpose of this RFA is to solicit applications that will utilize the non-human primate (NHP) resources maintained by the National Institute on Aging (NIA) Intramural Research Program (IRP). The NIA IRP has developed colonies of Rhesus monkeys and squirrel monkeys (described in the background section under Research Objectives) under either chronic or short-term caloric restriction protocols. These monkeys have been studied extensively and characterized by the NIA IRP. This RFA is to provide support for extramural investigators to perform additional studies on these cohorts of monkeys, thereby extending and expanding on the information about the effects of caloric restriction on the physiology of aging in NHP. 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), Caloric Restriction and Aging in NIA Primates, 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. There may be some restrictions imposed on successful applicants from foreign institutions based on laws governing export of tissue, cells, or live animals. MECHANISM OF SUPPORT This RFA will use the cooperative agreement (U01) mechanism. The cooperative agreement is an assistance mechanism in which substantial involvement of the NIA with the recipient is anticipated during the performance of the planned activity. The nature of the NIA's involvement is described under SPECIAL REQUIREMENTS. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant/awardee. The total project period for an application submitted in response to the present RFA may not exceed five years. The anticipated award date is September 2002. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated R01 applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE It is anticipated that a total of $1,000,000 will be available for the first year of support for this RFA and that 5-10 awards will be made. Because the nature and scope of the research proposed in response to this RFA may vary, it is anticipated that the sizes of awards will vary also. Awards and level of support depend on receipt of a sufficient number of applications of high scientific merit. Although this program is provided for in the financial plans of the NIA, awards pursuant to this RFA are contingent upon the availability of funds for this purpose. RESEARCH OBJECTIVES Background Caloric restriction (CR) is the one paradigm that has been demonstrated through extensive experimentation to extend lifespan in a variety of species, including flies, yeast and rodents. In addition to increased longevity, CR also has a positive effect on many metabolic and physiological variables in rodents, such as immune function, stress response, and spontaneous and induced tumor genesis. However, although there is a large body of experimental evidence for the benefits of CR in rodents, the mechanism by which CR effects those benefits has yet to be elucidated. It is also unknown at this time the extent to which the findings in rodents will be recapitulated in NHP. There have been limited studies on CR in NHP, due in part to the expense of maintaining the animals necessary to carry out such studies. The studies that have been done in NHP, primarily examining metabolic variables, have shown a remarkable level of agreement with the rodent data. It is important now to expand these studies in NHP to examine a broad range of variables to determine if CR has benefits to both lifespan and health- span in NHP and to investigate the mechanism(s) by which CR acts. The NIA IRP has colonies of Rhesus macaques and squirrel monkeys that have been maintained under CR protocols and extensively characterized for metabolic endpoints. CR was instituted at 10% per month until reaching 30% CR, the level at which they are maintained. These animals are now available to investigators in the extramural research community, as described below. IRP investigators have already generated a significant amount of data on these colonies, and a list of publications is available at the following website: http://www.grc.nia.nih.gov/branches/leg/rfa.htm. IRP investigators are available to any applicant for collaborative studies. The Rhesus macaque colony has two segments, a chronic (long-term) CR protocol and an acute (short-term) CR protocol. Under the chronic CR protocol, males were started in 1987-88 and females were started in 1992. For both genders, there are three (3) groups defined by the age at which CR was initiated: juvenile (1-2 years old); adult (3-5 years old); and aged (>17 years old). At the start of the study there were 10 animals in each cohort defined by gender/age at initiation/diet (CR or ad libitum (AL) fed controls), but due to mortality over the course of the study, actual numbers of animals available will vary. This group of animals is available primarily for noninvasive studies carried out at the NIA facility or in collaboration with NIA IRP investigators, with blood, tissue or cell samples transferred to the Principal Investigator’s home institution. Some exceptions may be made depending on the applications received. The Rhesus macaques in the acute CR protocol have undergone shorter CR protocols. There are three groups of animals: males initiated in the CR protocol in 1997, at 3-5 years of age; females initiated in the CR protocol in 1995 at 4-5 years of age; and males initiated in the CR protocol in 1996 at >18 years of age. Females were re-fed at AL levels for several months before returning to 30% CR by 12/1/00. Each group consists of 6 AL and 6 CR monkeys. These animals are available for terminal or invasive studies and may be approved for transfer to the Principal Investigator’s home institution. A colony of squirrel monkeys has been maintained under a chronic CR protocol since 1987. There are two age groups (males only), those initiated in CR as juveniles (1-4 years old) and those initiated as adults (5-10 years old). There are AL control groups for both groups and the sample size is approximately 7 per age/diet cohort. The squirrel monkeys are available for non-invasive research performed at the NIA facility or in collaboration with NIA IRP investigators. Research Objectives The research objectives of this RFA are very broad. The purpose of making this resource available is to stimulate research in all areas of study relating to the mechanism of action of CR in NHP. One goal is to determine if the health-span and lifespan benefits of CR observed in rodents are also observed in NHP. The second goal is to promote more mechanistic studies of CR to identify target systems, processes or molecules by which CR exerts its beneficial effects on healthy aging. To this end, many diverse areas of research are relevant, including investigations into maintenance of immune function with aging, behavioral studies, cognitive and motor function, sensory modalities including taste and olfaction, endocrine and neuroendocrine status, reproductive function, renal function, cardiovascular health, and hepatic function. The role of oxidative stress is another area of interest, since there is considerable evidence that oxidative stress is a major factor in aging and that CR reduces the level of oxidative stress in rodents. SPECIAL REQUIREMENTS Due to the limited nature of the resource, significant coordination of studies may be necessary to facilitate multiple investigations using the same animals. Therefore, experimental protocols and timing of experiments will be coordinated by an Advisory Panel as described below. Terms and Conditions of Awards The following terms and conditions will be incorporated into the award statement and provided to the Principal Investigator as well as the institutional official at the time of the award. These special Terms of Award are in addition to and not in lieu of otherwise applicable OMB administrative guidelines, HHS Grant Administrative Regulations at 45 CFR Parts 74 and 92, and other HHS, PHS and NIH Grant administration policy statements. The administrative and funding instrument used for this program is a cooperative agreement (U01), an assistance mechanism (rather than an acquisition mechanism) in which substantial NIH scientific and/or programmatic involvement with the awardee is anticipated during performance of the activity. Under the cooperative agreement, the NIH purpose is to support and/or stimulate the recipient’s activity by involvement in and otherwise working jointly with the award recipient in a partner role, but it is not to assume direction, prime responsibility or the dominant role in the activity. Consistent with this concept, the dominant role and prime responsibility for the activity resides with the awardee(s) for the project as a whole, although specific tasks and activities in carrying out the studies will be shared among the awardees and the Advisory Panel, which will be responsible for coordinating activities to allow multiple projects to efficiently and effectively utilize the primate colony. 1. Awardee Rights and Responsibilities Awardees have primary authorities and responsibilities to define objectives and approaches, to plan and conduct the research activities, and to analyze and publish results, interpretations and conclusions of their studies. NIH intramural investigators who are scientific collaborators with awardees will have the same rights and responsibilities as other investigators. Awardees will retain custody of and have primary rights to the data developed under these awards, subject to Government rights of access consistent with current HHS, PHS, and NIH policies. However, the awardee has the responsibility to submit the data to the Primate Aging Database, an NIA-sponsored database in development that will be available to all researchers. Timing of submission of the data will be coordinated between the Principal Investigator and the Advisory Panel, but will take place no later than the time of publication of the study results. Due to the significant investment the NIA has made in these animals, awardees also have the responsibility to provide excess collected tissue or blood to an NIA-approved tissue bank at the culmination of the study. If animals are used for terminal experiments, awardees will collect unused tissue, within reasonable limits, at necropsy and send it to a tissue bank as directed by the Advisory Panel. Awardees should attend an annual meeting at the NIA Gerontology Research Center in Baltimore MD, for the purpose of discussing preliminary results. 2. NIA Staff Responsibilities The Program Coordinator will be an Intramural NIA scientist with knowledge of the specific rhesus and squirrel monkey colonies. This individual will advise investigators and provide necessary expertise to ensure that the study goals can be met given the characteristics of the two colonies. The Program Coordinator is expected to have substantial scientific involvement during the course of these studies because of the knowledge of the colonies and expertise that will be shared with investigators. The Program Administrator will be an Extramural official with responsibility for administering the grant. This individual will also be a liaison member of the Advisory Panel (see below) in order to provide essential information concerning progress of the awards, to allow the Advisory Panel to make appropriate decisions about the continued use and sharing of the resources. An Advisory Panel will be established comprised of five extramural and intramural scientists who have expertise in primate colony management and use of NHP in research. Their role is to make recommendations to the NIA that will coordinate the use of the primate colonies among the awarded studies. None of the panel members may be part of a laboratory or unit that is seeking to use the resources of the subject primate colonies. The Advisory Panel will be convened at least once a year, with additional meetings and/or teleconferences as needed. The NIA reserves the right to terminate or curtail the study (or an individual award) in the event that significant mortality within the primate colonies renders the experimental approach invalid. 3. Collaborative Responsibilities The Advisory Panel will provide recommendations coordinating the experimental protocols to accommodate the needs of all investigators using the same animals. These animals are used in active research projects in the Intramural Research Program and funded studies must be compatible with the IRP studies in progress. Refer to the web site (http://www.grc.nia.nih.gov/branches/leg/rfa.htm) for descriptions of on-going projects. Data generated during the course of these studies must be made available to the Primate Aging Database. IRP Animal Care and Use Committee approval must be obtained for studies as described on the website. NIA IRP scientific staff are available for collaborative studies with active participation in the project execution. 4. Arbitration Any disagreement that may arise on scientific/programmatic matters (within the scope of the award), between award recipients and the NIA may be brought to arbitration. An arbitration panel will be composed of three members one selected by the individual awardee, a second member selected by NIA, and the third member selected by the two prior selected members. This special arbitration procedure in no way affects the awardee's right to appeal an adverse action that is otherwise appealable in accordance with the PHS regulations at 42 CFR Part 50, Subpart D and HHS regulation at 45 CFR Part 16. 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 the program staff listed under INQUIRIES by the letter of intent receipt date listed in the heading of this RFA. 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. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at: http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm Applicants may wish to place data collected under this RFA (PA) in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. 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 and 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. Applications are also available on the Internet at http://grants.nih.gov/grants/funding/phs398/phs398.html The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. 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 available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note that this sample label is in pdf format. Applicants should include in the budget funds to attend an annual meeting at the NIA Gerontology Research Center in Baltimore MD. If an NIH intramural investigator will be a scientific collaborator in the project, a formal letter of collaboration from the intramural scientist must be included as part of the grant application. The letter should describe the intramural scientist's collaborative work under the grant. The grant applicant is responsible for writing the section of the grant that describes the proposed collaboration within the grant, which the NIH investigator should see and approve. 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 the NIA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. 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, a process may be used by the initial review group in which applications receive a written critique and undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the 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 this study address an important problem? 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 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. Schedule: Letter of Intent Receipt Date: November 11, 2001 Application Receipt Date: December 11, 2001 Date of Initial Review: April, 2002 Review by Advisory Council: May, 2002 Anticipated Award Date: September 1, 2002 AWARD CRITERIA Applications recommended by the NIA Advisory Council will be considered for award based upon (a) scientific and technical merit; (b) program objectives; and (c) availability of funds. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding the application process or technical issues on the cooperative agreement mechanism to: Nancy L. Nadon, Ph.D. Head, Office of Biological Resources and Resource Development National Institute on Aging 7201 Wisconsin Avenue, GW 2C231 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: nadonn@exmur.nia.nih.gov Direct scientific inquiries regarding the primate colonies, including background information available, the CR protocols, and restrictions to research protocols, to: Mark Lane, Ph.D. National Institute on Aging Gerontology Research Center 5600 Nathan Shock Drive Baltimore MD 21224 Telephone: 301-594-1210 FAX: 301-480-0504 Email: ml124y@nih.gov Direct inquiries regarding fiscal matters and award concerns to: Linda Whipp Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: lw17m@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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