FRAILTY IN OLD AGE: PATHOPHYSIOLOGY AND INTERVENTIONS RELEASE DATE: May 13, 2003 PA NUMBER: PAS-03-122 March 2, 2006 (NOT-OD-06-046) Effective with the June 1, 2006 submission date, all R03, R21, R33 and R34 applications must be submitted through Grants.gov using the electronic SF424 (R&R) application. Parent R03 (PA-06-180) and R21 (PA-06-181) funding opportunity announcements have been issued for the submission date of June 1, 2006 and submission dates thereafter. Applications relating to R33 and R34 activities must be in response to NIH Institute/Center (IC)-specific announcements. EXPIRATION DATE for R21 Non-AIDS Applications: March 2, 2006 EXPIRATION DATE for R21 AIDS and AIDS-Related Applications: May 2, 2006 EXPIRATION DATE for All R01 Applications: May 22, 2006, unless reissued. National Institute on Aging (NIA) (http://www.nia.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.866 THIS PROGRAM ANNOUNCEMENT (PA) CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA The aim of this program is to foster biomedical research that will enhance our understanding of the complex biology and pathophysiology underlying the geriatric syndrome of frailty. A second goal is to foster development and testing of novel interventions targeting pathways believed to play an important mechanistic role in the development and progression of frailty. This PA is intended to foster clinical research, including integrative biomedical research, some of which will incorporate the tools of molecular and cellular biology in the study of function and clinical outcome, and studies in appropriate animal models. A long-term goal is to provide the groundwork for the possible prevention of frailty in older persons. RESEARCH OBJECTIVES Background The term "frailty" has been used clinically as a global concept to describe a condition, common in the very old, of impaired strength, endurance, and balance, vulnerability to trauma and other stressors, and high risk for morbidity, disability, and mortality. It may add clinical value in prognosis and decision-making because frail older persons may have additional adverse pathophysiologic or functional changes not captured fully by disease and disability definitions. If distinct pathophysiologic or functional changes can be shown to contribute to the clinical features of frailty, it may be possible to develop and test interventions that may provide additional benefits beyond those obtained from treatments from currently recognized diseases in old age. Operational definitions of frailty could greatly enhance research on its causes and consequences by providing precision and consistency within and among studies. Recently, a definition of frailty as a syndrome has been proposed, by which individuals are considered frail if they meet operationally defined criteria for at least three of the following five attributes: unintentional weight loss, muscle weakness, slow walking speed, exhaustion, and low physical activity (Fried et al.; J Gerontol Med Sci; 2001; 56A(3): M146-M156). Using this definition, the condition of frailty was found to overlap only partially with the presence of comorbidity or disability. A substantial proportion of frail older persons did not meet common criteria for either comorbidity or disability. Frailty, as defined above, has independent predictive value for mortality, increases in disability in activities of daily living, and hospitalization, even after adjusting for disease diagnoses and other factors. There is also evidence that frailty thus defined may result from pathologic processes acting independently from the effects of diseases present in the elderly. Recent reports indicate that frailty is associated with elevated circulating levels of markers of inflammation (C-reactive protein) and coagulation (fibrinogen and factor VIII) (Walston et al.; Arch Intern Med; 2002; 162: 2333-2341). These markers were linked to frailty even in the absence of two of the most prevalent comorbid conditions in older persons, cardiovascular disease and diabetes. Other operational definitions of frailty, using differing or additional criteria, may also be useful in capturing additional clinically important aspects of the weakness, vulnerability to stress, and other decrements implied by the general concept of frailty, and in identifying important pathophysiologic processes. Research focused on individual components of syndromic definitions of frailty (e.g., weight loss, exhaustion) may also be useful in clarifying its pathophysiology. A variety of factors may contribute to frailty or to one or more of its specific features. These include inflammatory, musculoskeletal, cardiorespiratory, metabolic, hematologic, neurologic, immunologic and endocrine functions. Few of these have been studied in regard to frailty. Inflammatory factors, such as interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), and C-reactive protein (CRP), have been the focus of several studies. These studies found associations between elevations in inflammatory markers and low muscle strength, exhaustion, slow walking speed, and low physical activity. Pathways mediated by angiotensin converting enzyme (ACE) may be important in the pathophysiology of frailty. Studies on ACE inhibitors in frail older women suggest that they may protect against muscle weakness. ACE inhibitors have been suggested to play an important role in factors that could contribute to frailty, including inflammation, fibrinolysis, oxidative stress, and endothelial dysfunction. Dysregulation of dynamic interactions among physiologic systems may also play an important role in frailty (Lipsitz LA; J Gerontol A Biol Sci Med Sci; 2002; 57(3): B115-125). Most studies to date on potential factors contributing to frailty have been associational and have not clearly established cause-and-effect relationships. For example, an important research question that needs to be answered is whether elevated levels of inflammatory factors actually contribute to the development and progression of frailty, or whether they rise as a consequence of some aspect of frailty, or in response to another, yet to be identified, factor that contributes to frailty. Controlled intervention studies can be valuable in clarifying the causal role of factors associated with frailty, as well as in determining effects of interventions on frailty itself or its components. Both types of information are useful preliminary data for possible larger clinical prevention or therapeutic trials. There is evidence that some available interventions affect factors that may contribute to frailty. Physical activity has effects on chronic inflammation as well as strength. Statins and ACE inhibitors have effects on markers of chronic inflammation. ACE inhibitors may also affect muscle strength and other systems that may be involved in the pathophysiology of frailty. Thiazolidinedione oral hypoglycemic agents have effects on muscle and inflammation. The effects of different types of anti-inflammatory agents on components of frailty have not yet been thoroughly examined. Animal models have begun to be developed that could greatly enhance opportunities for research on frailty. For example, an aging rodent model has been used to assess the longitudinal changes in physical performance and their relationship to longevity (Carter et al.; J Gerontol Biol Sci; 2002; 57A(5): B193-B197). Knowledge to be achieved NIA encourages submission of R01 applications for projects to elucidate the pathophysiologic basis of frailty. Studies may address frailty defined as a syndrome, as described in the preceding section, or on one or more components of such a syndrome (e.g., weight loss or exhaustion), or alternative phenotypic definitions of frailty. Proposed projects may include observational studies (including prospective studies), mechanistic studies, small-scale human intervention studies, and studies in animal models. Studies designed to allow conclusions regarding pathophysiologic effects, beyond mere associations, are very strongly encouraged. An integrative approach to frailty, through collaboration between basic and clinical scientists, is highly desirable. Topics of interest include, but are not limited to: o Role of inflammatory factors in frailty, including their role in muscle weakness, weight loss, low physical activity, and other biological and behavioral phenotypes related to frailty. Studies on circulating factors and factors in specific tissues are encouraged. Studies on interactions of inflammatory factors with other cellular processes (e.g., apoptosis) and physiologic processes (e.g., endocrine and metabolic regulation) are encouraged; o Effects of angiotensin converting enzyme and drugs and other factors modulating its actions on the development of components of frailty; o Roles of musculoskeletal, cardiorespiratory, metabolic, bioenergetic, hematologic, neurologic, immunologic, and endocrine factors and their interactions. Roles of factors related to regulation of mood and affect (e.g., neuroendocrine factors involved in depression) and other psychological factors are also of interest; o Role of cell loss, apoptosis, and loss of stem cells (e.g., muscle satellite cells)in specific tissues in the development of frailty or on one or more of its components; o Contributions to frailty by mechanisms postulated to be important in aging processes; e.g., oxidative damage; o Effects of genetic polymorphisms on risk for frailty or on one or more of its components, and on responses to interventions to ameliorate frailty or one of its components; o Explorations of the role in frailty of dysfunctional regulation of dynamics of physiologic responses to stressors or other perturbations; o Interrelationships between individual phenotypes of frailty or components of frailty, defined as a syndrome, such as: synergistic effects on outcomes; identifying common causal mechanisms underlying several components; and/or mutually reinforcing relationships between components (e.g., positive feedback loops); o Development and use of appropriate aging animal models to study etiologic and pathophysiologic pathways postulated to play important roles in frailty, and to conduct pre-clinical testing of novel interventions; o Small-scale human intervention studies (e.g., both drug, endocrine, or lifestyle) to better characterize the importance of various biologic pathways in frailty including: identifying potential targets for therapeutic intervention; and to identify promising intervention studies for larger, more definitive trials; and o Longitudinal human studies to clarify the sequence of changes leading to frailty and its clinical consequences, including interactions with effects of specific chronic diseases. These topics are neither prioritized nor meant to be restrictive. Principal Investigators are encouraged to submit applications in any area of research responsive to the general research objectives of the PA. MECHANISM OF SUPPORT This PA will use the NIH research project grant (R01) award mechanism and the exploratory/developmental research project award (R21)mechanism of support. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. The total project period for an application submitted in response to this PA may not exceed five years. Applicants pursing an exploratory/developmental research project award (R21) should follow the guidelines described in the program announcement entitled NIH EXPLORATORY/DEVELOPMENTAL RESEARCH GRANT AWARD (R21). This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm. Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. This program does not require cost sharing as defined in the current NIH Grants Policy Statement at http://grants.nih.gov/grants/policy/nihgps_2001/part_i_1.htm FUNDS AVAILABLE NIA intends to commit $1.8 million in total costs for the first year of funding for applications submitted in response to this PA for the following three receipt dates: October 1, 2003, February 1, 2004, and June 1, 2004. Applications received after the June 1, 2004 receipt date (except for amended applications submitted for the July 1, 2004 receipt date) will not compete for set-aside funding. These applications will compete for funding with all other applications assigned to NIA. Awards made will be contingent upon availability of funds and the receipt of a sufficient number of applications of outstanding scientific and technical merit. ELIGIBLE INSTITUTIONS You may submit an application if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community-based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with his or her institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues: o Direct your questions about scientific/research issues to: Andre J. Premen, Ph.D. Geriatrics & Clinical Gerontology Program National Institute on Aging Gateway Building, Room 3C-307 Bethesda, MD 20892-9205 Telephone: (301) 496-6761 FAX: (301) 402-1784 Email: PremenA@nia.nih.gov o Direct your questions about financial or grants management matters to: Ms. Linda Whipp Grants Management Officer Grants and Contracts Management Office National Institute on Aging Gateway Building, Room 2N212 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: WhippL@nia.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov APPLICATION RECEIPT DATES: Applications submitted in response to this PA will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of the NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff member at least six weeks before submitting the application, i.e., as you are developing plans for the study; 2) Obtain agreement from the IC staff member that the IC will accept your application for consideration for award; and 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: 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) APPLICATION PROCESSING: Applications must be mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The Center for Scientific Review (CSR) will not accept any application in response to this PA 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 a substantial revision of an application already reviewed, but such an application must include an Introduction addressing the previous critique. Although there is no immediate acknowledgement of the receipt of an application, applicants are generally notified of the review and funding assignment within 8 weeks. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures http://www.csr.nih.gov/refrev.htm will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o Receive a second level review by 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your 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. 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? APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? INNOVATION: Does the project employ novel concepts, approaches or methods? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? INVESTIGATOR: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the Principal Investigator and other researchers (if any)? ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, the following items will be considered in the determination of scientific merit and the priority score: PROTECTION OF HUMAN SUBJECTS FROM RESEARCH RISK: The involvement of human subjects and protections from research risk relating to their participation in the proposed research will be assessed. (See criteria included in the section on Federal Citations, below). INCLUSION OF WOMEN, MINORITIES AND CHILDREN IN RESEARCH: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research will be assessed. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria in the sections on Federal Citations, below). CARE AND USE OF VERTEBRATE ANIMALS IN RESEARCH: If vertebrate animals are to be used in the project, the five items described under Section f of the PHS 398 research grant application instructions (rev. 5/2001) will be assessed. ADDITIONAL CONSIDERATIONS BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS HUMAN SUBJECTS PROTECTION: Federal regulations (45CFR46) require that applications and proposals involving human subjects must be evaluated with reference to the risks to the subjects, the adequacy of protection against these risks, the potential benefits of the research to the subjects and others, and the importance of the knowledge gained or to be gained. http://www.hhs.gov/ohrp/humansubjects/guidance/45cfr46.htm . MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html. INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: 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 clinical research projects unless a clear and compelling justification is 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 clinical research should read the "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines is available at http:// grants.nih.gov/grants/funding/women_min/guidelines_amended_10_2001.htm. The amended policy incorporates: the use of an NIH definition of clinical research; updated racial and ethnic categories in compliance with the new OMB standards; clarification of language governing NIH-defined Phase III clinical trials consistent with the new PHS Form 398; and updated roles and responsibilities of NIH staff and the extramural community. The policy continues to require for all NIH- defined Phase III clinical trials that: a) all applications or proposals and/or protocols must 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) investigators must report annual accrual and progress in conducting analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/ NOT-OD-00-039.html. 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 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. STANDARDS FOR PRIVACY OF INDIVIDUALLY IDENTIFIABLE HEALTH INFORMATION: The Department of Health and Human Services (DHHS) issued final modification to the "Standards for Privacy of Individually Identifiable Health Information", the "Privacy Rule," on August 14, 2002. The Privacy Rule is a federal regulation under the Health Insurance Portability and Accountability Act (HIPAA) of 1996 that governs the protection of individually identifiable health information, and is administered and enforced by the DHHS Office for Civil Rights (OCR). Those who must comply with the Privacy Rule (classified under the Rule as "covered entities") must do so by April 14, 2003 (with the exception of small health plans which have an extra year to comply). Decisions about applicability and implementation of the Privacy Rule reside with the researcher and his/her institution. The OCR website (http://www.hhs.gov/ocr/) provides information on the Privacy Rule, including a complete Regulation Text and a set of decision tools on "Am I a covered entity?" Information on the impact of the HIPAA Privacy Rule on NIH processes involving the review, funding, and progress monitoring of grants, cooperative agreements, and research contracts can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-025.html. 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. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. 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 PA 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/. AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance at http://www.cfda.gov/ and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under the authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. All awards are subject to the terms and conditions, cost principles, and other considerations described in the NIH Grants Policy Statement. The NIH Grants Policy Statement can be found at http://grants.nih.gov/grants/policy/policy.htm. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and to discourage the 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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