PA-00-081: AGING, OXIDATIVE STRESS AND CELL DEATH

Department of Health
and Human Services (HHS)

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AGING, OXIDATIVE STRESS AND CELL DEATH Release Date: March 23, 2000 PA NUMBER: PA-00-081 National Institute on Aging THIS PA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO THE STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS PROGRAM ANNOUNCEMENT. PURPOSE The purpose of this Program Announcement (PA) is to encourage the submission of applications to support research on the relationship between oxidative stress and apoptosis, and how these biological processes are involved in aging and/or change with age. This program announcement supersedes two PAs issued earlier by the NIA: Molecular mechanisms of cell death during aging, and PA-93-017, Oxidative damage, antioxidant defense, and aging. Although the National Institute of General Medical Sciences is not participating in this program announcement, that Institute continues to be interested in receiving applications on basic mechanisms of programmed cell death and oxidative stress when these applications do not focus on aging mechanisms. 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 Program Announcement, Aging, oxidative stress, and cell death, 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 The mechanism of support will be the National Institutes of Health (NIH) individual research project grant (R01). Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this PA may be up to 5 years. For R01 applications requesting up to $250,000 direct costs per year, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by NIH. Complete and detailed instructions and information on Modular Grant applications can be found at: http://grants.nih.gov/grants/funding/modular/modular.htm. Applications that request more than $250,000 in any year must use the standard PHS 398 (rev. 4/98) application instructions. FUNDS AVAILABLE Applications submitted in response to this Program Announcement, and assigned to the NIA, will compete with all other applications assigned to the NIA. No funds have been set aside for funding applications submitted in response to this PA. The award of grants pursuant to this PA is contingent upon the availability of funds for this purpose and the receipt of meritorious applications. RESEARCH OBJECTIVES Cell death in multicellular organisms takes place in a variety of different circumstances. For example, the death of certain cells may occur as part of a developmental program e.g. during nervous system development, in connection with organ involution or regression, when potentially harmful cells such as neoplastic or virus-infected cells are targeted for destruction by surveillance systems, in response to the absence of critical growth factors, or as a consequence of toxic or harmful environmental conditions. When cells are damaged in mitotically active tissues, they can usually be replaced by division of neighboring healthy cells. However, when post-mitotic cells are damaged and die, cell replacement may not be possible and the function of the tissue is eventually compromised, as occurs in the neurodegenerative disorders such as Alzheimer’s and Parkinson’s diseases. Oxidative damage due to the endogenous production of reactive oxygen species by mitochondria is a common and ubiquitous form of oxidative stress in most mammalian cells. However, these cells have robust systems for both detecting and repairing this damage, particularly in the case of DNA. When confronted by damaged DNA, cells either set about repairing themselves or commit suicide through apoptosis. The checkpoint proteins p53 and ATM (ataxia telangiectasia mutated) are designed to block DNA replication of damaged DNA until repair of the DNA has been accomplished (Weinert, 1998), and ATM deficiency results in the lack of p53 induction by ionizing radiation, a DNA damaging agent (Barlow et al., 1997). When these checkpoint proteins are missing or defective, the result may be inappropriate cell growth, as in cancer (Levine, 1997, Venkitaraman, 1999), or inappropriate cell loss, as in ataxia telangiectasia. Alternatively, the damage may be so extensive as to preclude adequate repair, leading to a variety of degenerative diseases. It is now clear that cell death, especially apoptotic cell death, plays a role in a large variety of age-related pathological changes (Warner et al., 1997). Thus, understanding how a mammalian cell recognizes and repairs damage, and thereby maintains homeostasis, or conversely fails to repair the damage, is critical to understanding the biological basis of aging in a variety of cells and tissues. In fact, fibroblasts taken from individuals with Werner syndrome, a premature aging syndrome, have an attenuated p53- mediated apoptotic response (Spillare et al., 1999). The importance of this question is further highlighted by the recent paper showing that a mutation in the p66shc protein not only blocks induction of oxidative repair functions and increases the resistance of the mice to paraquat, but also extends the life span of the mice by 30% (Migliaccio et al., 1999). Also of particular interest is the role of mitochondria in these processes. Mitochondria are not only a major source of endogenous production of reactive oxygen species, but the release of cytochrome C from mitochondria also induces the entire caspase cascade involved in apoptosis (Slee et al., 1999). Furthermore, critical mitochondrial proteins involved in production of cytosolic ATP appear to be targets of increasing oxidative damage during aging (Yan et al., 1997), but it is not clear if and how this self-inflicted damage actually leads to mitochondrial leakage of cytochrome C and induction of apoptosis. In neurons, following neurotrophic factor removal, a key event is the translocation of BAX from the cytosol to the mitochondria with subsequent release of cytochrome C and activation of caspases (Putcha et al., 1999). Mitochondrial dysfunction due to oxidative damage and leading to cell death may thus be a unifying basic mechanism involved in neurodegeneration (Beal, 1998). The major objectives of this program announcement include, but are not limited to applications designed to address one or more of the following research questions: o Are there age-related changes in apoptotic potential? o What is the role of apoptosis in adverse age-related changes? o How does damage to DNA, proteins and lipids induce the apoptotic process? o Under what conditions, if any, is cell death preferable to survival of a damaged cell? o How does mitochondrial dysfunction contribute to both oxidative stress and apoptosis? o Identification of single nucleotide polymorphisms in genes such as those for ATM, p53, caspases, bcl-2 family members, caspase inhibitors, and DNA repair enzymes, and/or their influence on any of the above questions. o Use of transgenic and/or knockout mice to evaluate the role of any of these gene products in oxidative stress, mitochondrial dysfunction, macromolecular repair processes and apoptosis, with special emphasis on the role of these processes in aging. REFERENCES Barlow, C. et al. 1997. ATM selectively regulates distinct p53-dependent cell-cycle checkpoint and apoptotic pathways. Nature Genetics 17: 453-456. Beal, M.F. 1998. Mitochondrial dysfunction in neurodegenerative diseases. Biochem. Biophys. Acta 1366: 211-223. Levine, A.J. 1997. p53, the cellular gatekeeper for growth and division. Cell 88: 323-331. Migliaccio, E., et al. 1999. The p66shc adaptor protein controls oxidative stress response and life span in mammals. Nature 402: 309-313. Putcha G.V., et al. 1999. BAX translocation is a critical event in neuronal apoptosis: regulation by neuroprotectants, BCL-2, and caspases. J. Neurosci. 19: 7476-7485. Slee, E.A., et al. 1999. Ordering the cytochrome C-initiated caspase cascade: Hierarchial activation of caspases-2, -3, -6, -7, -8 and 10 in a caspase-9-dependent manner. J. Cell Biol. 144: 281-292. Spillare, E.A. et al. 1999, p53-mediated apoptosis is attenuated in Werner syndrome cells. Genes Dev. 13: 1355-1360. Venkitaraman, A.R. 1999. Breast cancer genes and DNA repair. Science 286: 1100-1102. Warner, H.R., et al. 1997. What does cell death have to do with aging? J. Am. Ger. Soc. 45: 1140-1146. Weinert, T. 1998. DNA damage and checkpoint pathways: Molecular anatomy and interactions with repair. Cell 94: 555-558. Yan, L.-J., et al., 1997. Oxidative damage during aging targets mitochondrial aconitase. Proc. Natl. Acad. Sci. USA, 94: 11168-11172. 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 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). 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, Volume23, Number 11, March 18, 1994, http://grants.nih.gov/grants/guide/notice-files/not94-100.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES Applications are to be submitted on grant application form PHS 398 (rev. 4/98). and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892- 7910, Phone (301) 710-0267, Email: GRANTSINFO@NIH.GOV. Applications are also available on the internet at http://grants.nih.gov/grants/funding/phs398/phs398.html. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that they must contact the Institute or Center (IC) program staff before submitting the application, i.e., as plans for the study are being developed. Furthermore, applicants must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, applicants must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. This policy requires applicants to obtain agreement for acceptance of any such application and/or any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.html. Submit a signed, typewritten, original of the application, including the checklist and five signed photocopies 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) The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. SPECIFIC APPLICATION INSTRUCTIONS FOR MODULAR GRANTS The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in- time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list key project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/ organizations with whom consortium or contractual arrangements have been made, the percent effort of key personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm. - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years, - List selected peer-reviewed publications, with full citations. o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications that are complete will be evaluated for scientific and technical merit by an appropriate peer review group convened in accordance with NIH peer review procedures. As part of the initial merit review, all applications will 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 applications under review, will be discussed, assigned a priority score, and receive a second level review by the appropriate national advisory council or board. The review criteria below are required for unsolicited research project grant applications. To the extent reasonable they are also to be used for other mechanisms. 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 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. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be considered in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program priority. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Huber R. Warner, Ph.D. Biology of Aging Program National Institute on Aging 7201 Wisconsin Avenue Suite 2C231 - MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: warnerh@exmur.nia.nih.gov or Bradley Wise, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue Suite 3C307 - MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: wiseb@exmur.nia.nih.gov Direct inquiries regarding fiscal matters to: Crystal Ferguson 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: fergusoc@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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