PROTEIN STRUCTURE AND FUNCTION IN AGING & LATE-LIFE DISEASE Release Date: April 14, 1999 RFA: AG-99-005 P.T. National Institute on Aging Letter of Intent Receipt Date: April 30, 1999 Application Receipt Date: June 23, 1999 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE The National Institute on Aging (NIA) invites applications for research project grants (R01) to support basic research on protein structure, function, and integrity during the aging process and in late-life disease. The goal of this RFA is to solicit applications that will examine, over the life-course, certain aspects of protein and peptide integrity that may change with age. Proteins are responsible in part for maintaining functional stability and homeostasis of cells and tissues. During aging there are many opportunities for appropriately transcribed peptides and proteins to become structurally altered. Accumulation of altered proteins may be correlated with a loss of function or, in some cases, a gain of inappropriate or toxic function. Therefore, it is critical to identify the specific alterations of proteins occurring during aging and in disease processes, and to define the role these alterations play in age- related and disease-related pathologies. The ability of a protein to perform its function in the cell depends in part upon its ability to assume and retain its proper functional conformation. The proper conformation is achieved by regulated folding during synthesis, aided by chaperone proteins. Mutations and other changes that divert proteins from their normal folding pathways or that destabilize their native state may underlie several human diseases. For example, alterations of the thermodynamic stability in folding of the native state and critical folding intermediates may prevent folding into a functional conformation on a biological scale. Cellular quality control machinery must then recognize misfolded and/or partially folded products and either refold them or mark them for recycling. Off-pathway traps can be caused by aggregation, mis-targeting into an inappropriate cellular location, or proteolysis. Proteins and peptides that are aggregated (for example, into amyloid plaques) or cross-linked are often resistant to degradation. The formation of these deposits, rather than the lack of native protein, may be responsible for, or contribute significantly to, cellular pathology. Accumulation of aggregated proteins thus may play an important role in the aging process and in age-related diseases. A multi-disciplinary approach to the study of protein structure and integrity of function in aging and age-related diseases is envisioned. By using a combined approach and techniques from physics, biophysics, chemistry, biochemistry and biology it should be possible to accelerate the rate of research progress to yield a greater in-depth understanding of the molecular changes in proteins that can take place in aging and in age-related diseases. The goal, ultimately, would be to intervene in these age-related diseases and processes. 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 foreign and domestic for-profit and non-profit organizations, public and private, such as universities, colleges, 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. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT This RFA will use the individual research project grant (R01) mechanism. However, specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. 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. Complete and detailed instructions and information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. Applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. A typical modular grant application will request the same number of modules in each year. Application budgets will be simplified. Detailed categorical budget information will not be submitted with the application; budget form pages of the application kits will not be used. Instead, total direct costs requested for each year will be presented. Information, in narrative form, will be provided only for Personnel and, when applicable, for Consortium/Contractual Costs. See section on application instructions below. Additional narrative budget justification will be required in the application only if there is a variation in the number of modules requested. There will be no routine escalation for future years. In determining the total for each budget year, applicants should first consider the direct cost of the entire project period. Well-justified modular increments or decrements in the total direct costs for any year of the project that reflect substantial changes in expected future activities may be requested. For example, purchase of major equipment in the first year may justify a higher overall budget in the first, but not in succeeding years. Other Support pages of the PHS 398 will not be submitted with the application. Information on research projects ongoing or completed during the last three years of the principal investigator and key personnel will be provided as part of the "Biographical Sketch." This information will include the specific aims, overall goals and responsibilities and should include Federal and non-Federal support. This information will be used by reviewers in the assessment of each individuals qualifications for a specific role in the proposed project. Following peer review, information about Other Research Support will be requested by NIH from the applicant for applications being considered for award. Additional budget information will be requested only under special circumstances. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and will be reviewed according to the usual peer review procedures. This research topic area also might be addressed using multidisciplinary approaches benefiting from some level of formalized interaction to facilitate the exchange of data, materials and ideas. Thus, the submission of linked investigator-initiated interactive research project grants (IRPG) in response to this RFA is encouraged, as appropriate. Guidelines to aid in the development and submission of an IRPG are available from NIA staff or in electronic form at http://grants.nih.gov/grants/guide/pa-files/PA-96-001.html. Because each research project of an IRPG is an independent application, like the typical R01, each project must stand on its own scientifically. The collaboration may involve limited shared resources and a modest amount of support for core functions may be requested at the time of submission by only one of the entities. Thus, for some scientifically based collaborative efforts, the exchange of data, materials, and ideas is more important than extensive, shared, physical resources or central oversight as in a program project grant application. However as described below, the additional cost of the core together with the cost of the research component, whether as modules or actual cost estimates must not exceed the upper limit of $500,000 (total cost). The total project period for an application submitted in response to the present RFA may not exceed four years. The anticipated award date is March 1, 2000. FUNDS AVAILABLE It is estimated that as much as $2,000,000 will be available to support from four to six new research awards. Awards issued under this RFA are contingent upon the receipt of highly meritorious applications and availability of funds for this purpose. For the first year applicants may request a maximum of five hundred thousand dollars (total cost). Budgets for all subsequent years should be constructed so that the total direct costs are less than or equal to the inflation-adjusted first year cost, or where proposed costs exceed the inflation- adjusted prior year cost are rigorously justified. RESEARCH OBJECTIVES Background It is important to know more about how proteins fold under native conditions as well as under abnormal conditions, and how folding is affected during aging and by disease. It is critical to know the effects of mutations on structure and folding near critical regions in a protein versus polymorphisms dispersed along the protein backbone, but having little or no apparent effect on the function of a protein. Membrane-spanning and membrane-associated proteins present particular challenges. It is also important to understand more precisely how chaperone proteins are involved in the initial protein folding process or in the re-folding of malformed proteins. Likewise, the microenvironment, including pH, the presence/absence of certain ions, availability of co-factors, and the extent of post-translational modification in both the extracellular and intracellular compartments may influence the process of folding or of subsequent aggregation. The resultant changes can be simple or complex, i.e., related to changes in expression (simple stoichiometry) or to inappropriate intermolecular interactions. Ultimately, such alterations could have an effect on protein stability and function. The role of protein degradation and ubiquitination of incorrectly folded, non-functional proteins and aggregates is also of interest. With respect to this announcement, a more complete understanding of all of the foregoing elements is needed in reference to aging and, especially, in regard to diseases with an onset late in life. For example, it will be important to know more about factors such as tissue concentrations of glucose and hormones that increase, decrease or otherwise influence the rate and extent of post- translational modifications of proteins. How do age and cell type influence the rates of synthesis and folding, and degradation of proteins? Stemming from those considerations, what are the physiological and functional consequences of the physical changes (to secondary and higher order conformations) of a protein s structure? These could range from specific effects on a protein's original function to global alterations in cellular metabolism (e.g., the initiation of apoptotic programs). Effective interventions for some diseases of aging will likely require a more complete understanding of the structure of proteins and peptides that change in conformation with age, resulting in cellular dysfunction. To that end an interdisciplinary approach is warranted. For example, the structural chemist and the biologist may need to collaborate with the biophysicist. Such collaborations in the context of linked R01s, especially, may best facilitate the development of new approaches to observe or monitor aspects of protein folding. In this way the field should gain insights on: approaches for obtaining structural maps of membrane and cytosolic proteins involved in disease; new imaging techniques as probes of macromolecular interactions; and molecular modeling and therapeutic approaches for the prevention of deposition and the removal of abnormally folded proteins. Such research may lead to an ability to predict, at the molecular level, associations between proteins, and to prevent or reverse the pathogenic alterations that lead to age-related disease. The research objectives for the types of research and experimental approaches that are being sought by this RFA may be either narrowly focused from the perspective of a single discipline or broadly interdisciplinary. Examples of some research topics are listed below. Such examples are intended to be illustrative, and not restrictive or prescriptive. o Studies which assess changes in post-transcriptional events (such as assembly, folding, and trafficking) and functioning of proteins (cytosolic as well as membrane-spanning and membrane-associated) with age and age-associated diseases, specifically in the processes that fail with age. o Structural studies of proteins focused on the coordinated contributions of chaperones, repair processes, degradation and non-enzymatic reactions with respect to a particular aging process. o Development of new approaches to observe or monitor aspects of protein folding relevant to issues in aging. o Development of novel interventions designed to interrupt or reverse aggregation or cross-linking of proteins that accumulate with age. 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, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects' research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. However, the scientific goals of this RFA are focused on aging. In describing the plan to recruit human subjects, investigators may cite a focus on aging as the justification for why will be excluded. In this regard applicants may use Justification 1, the research topic to be studied is irrelevant to children, from the policy announcement. LETTER OF INTENT Prospective applicants are asked to submit, by April 30, 1999, 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 NIA staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent to: D. Stephen Snyder, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Room 3C307, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: SnyderD@exmur.nia.nih.gov APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. Applications kits 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 World Wide Web 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. 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. BUDGET 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 - Use 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. 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. 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. Provide an additional narrative budget justification for any variation in the number of modules requested. 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 current position(s) and then previous positions; - List selected peer-reviewed publications, with full citations; - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. 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. It is important to identify all exclusions that were used 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. APPLICATIONS NOT CONFORMING TO THESE GUIDELINES WILL BE CONSIDERED UNRESPONSIVE TO THIS RFA AND WILL BE RETURNED WITHOUT FURTHER REVIEW. 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, SUITE 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. 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. Applications must be received by June 23, 1999. 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 for responsiveness by the NIA. Incomplete applications will be returned to the applicant without further consideration. To be considered responsive to this solicitation an application must include a statement summarizing the specific age-relatedness of the proposed investigation. That statement should be placed within the "background and significance" section of the proposal. 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. If one (or more) component(s) of a set of linked IRPG R01s is considered unresponsive to the RFA only the application deemed responsive will be evaluated. 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 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. 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. o 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? o 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? o 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? o 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)? o 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? Where appropriate, the initial review group will look for evidence of interdisciplinary collaboration. The review group will also examine: the appropriateness of proposed project budget and duration; the adequacy of plans to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research, and plans for the recruitment and retention of subjects; the provisions for the protection of human and animal subjects; and the safety of the research environment. AWARD CRITERIA Awards will be made on the basis of scientific and technical merit as determined by peer review and reflected in the priority score or percentile, the availability of funds, and programmatic priorities will be used to make award decisions. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic (scientific) issues to: For applications with a primary emphasis on the biology of aging contact: Pamela Starke-Reed, 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: StarkeP@exmur.nia.nih.gov For applications with a primary emphasis on the neuroscience of aging contact: D. Stephen Snyder, Ph.D. Neuroscience and Neuropsychology of Aging Program National Institute on Aging Gateway Building, Suite 3C307 7201 Wisconsin Ave., MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: SnyderD@exmur.nia.nih.gov Direct inquiries regarding fiscal matters to: Ms. 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 the Public Health Service Act, Title IV, Part A (Public Law 78-410), as amended by 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 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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