AGE-RELATED CHANGES IN TISSUE FUNCTION: UNDERLYING BIOLOGICAL MECHANISMS (R01) RELEASE DATE: July 12, 2002 PA NUMBER: PA-02-128 (see reissuance PA-03-147) EXPIRATION DATE: June 30, 2003, unless reissued. National Institute on Aging (NIA) ( National Institute on Deafness and Other Communication Disorders (NIDCD) ( National Institute of Dental and Craniofacial Research (NIDCR) ( National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) ( THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanisms of Support 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 This program announcement is to solicit applications on biological mechanisms of aging in tissues and organs. Projects are encouraged that significantly advance basic biology research to understand how and why changes take place in tissues with age and how those changes relate to altered tissue and organ function. Projects that focus on molecular aspects, as well as cellular aspects of tissue aging, are encouraged. Projects that emphasize molecular and cellular changes that are common among tissues with aging are also encouraged, as are projects that compare mechanisms of aging change in different tissues. Projects must have a clear relevance to aging to be considered under this Program Announcement. RESEARCH OBJECTIVES Background Many tissues, organs and organ systems show decrements in function with age. These decrements in function disadvantage the aging population, leading to decreases in health and activity and subsequent decreases in the ability of individuals to take care of themselves and in overall quality of life. Understanding the biological mechanisms of change with age will likely lead to treatment or prevention of some resulting disabilities and improved quality of life for elderly citizens. Most organs and tissues of the body exhibit some age-related decline in function or increase in disease incidence. For example, muscle strength declines with age. In addition, bones often weaken, depending both on age and changes in hormonal status. The fragility imposed by weakened muscles and bones can result in falls that may be disabling. The skin undergoes visible changes, but also may exhibit impaired wound healing, a threat to health. The growth rate of prostate tissue accelerates in middle-aged men leading to the diseases of benign prostatic hyperplasia and possibly prostate cancer that are so common in older men. Female reproductive aging processes lead to sharply reduced estrogen levels in middle-aged menopausal women, this in turn increases the risk for chronic diseases with increased morbidity and mortality. Serum levels of some hormones (e.g., growth hormone, dehydroepiandrosterone, testosterone) decline with age, while other hormones (e.g., gonadotropins, insulin) increase with age. For the most part, the functional consequences of these age-related changes in hormone levels are not well understood. It has also been established that overall immune function declines with age, leading to an increased susceptibility to various infectious diseases. Age-associated changes are evident in both T and B lymphocytes and at higher organizational levels including the thymus, bone marrow and germinal centers. However, the events and mechanisms underlying these phenomena are not well understood. Nervous system function declines with age leading to impairments in cognition, motor, sensory and other behaviors. Atrophy of brain tissue and changes in neural circuitry may contribute to the functional decline. Much needs to be learned about the cellular and molecular mechanisms responsible for the selective vulnerability of brain cells and regions to age-dependent dysfunction and neurodegeneration, as occurs in Alzheimer"s disease. Some of the changes seen with aging are more or less prominent in different racial groups or between genders. For example, bone density is higher and the risk for low bone mass and osteoporosis is lower in African American women than in Caucasian women. Both men and women experience osteoporosis, but women are at higher risk due to relatively sharp changes in hormonal levels associated with menopause. Older African American men are at higher risk for prostate cancer than Caucasians. Distribution and metabolism of adipose tissue are associated with risk of metabolic disease, these differ in obese menopausal African American, American Indian and Caucasian women. The molecular underpinnings of these differences in age-related changes need to be identified. The Biology of Aging Program, Neuroscience and Neuropsychology of Aging Program, and Geriatrics and Clinical Gerontology Program at the NIA encourage applications that will elucidate the basic biological causes and consequences of changes in tissue and organ function related to aging and identify commonalities, distinguishing features, and interactions between them. The Biology of Aging Program supports work through the Cardiovascular Biology, Endocrinology, Immunology, Musculoskeletal Biology, and Physiology Programs. These programs encompass most tissues and organs of the body, outside of the nervous system. The Neuroscience and Neuropsychology of Aging Program supports work on the nervous system, including fundamental neuroscience, integrative neurobiology, motor and sensory systems, cognition and the dementias of aging, particularly Alzheimer"s disease. The Geriatrics and Clinical Gerontology Program supports research on health and preventing and treating disease in the aged, as well as research on aging over the human life span and its relationship to health outcomes. As all of these programs cover a broad spectrum of research, areas mentioned in the paragraphs above are examples and are not intended to limit the possible areas of research support requested in response to this announcement. The NIDCD, NIDCR, and NIDDK each support research in their respective areas of interest. Applicants can obtain further information for each of the sponsoring Institutes at the web addresses listed on the first page of this announcement or by contacting the respective program contact listed in this announcement. Objectives and Scope This Program Announcement is intended to encourage basic research into processes that lead to altered function of tissues and organs as a result of aging. Research that takes maximal advantage of emerging genetic, genomic and proteomic information on humans and other animals to understand changes that occur with aging is particularly encouraged. The following examples illustrate areas of research that are of interest, but serve as examples only, and are not exclusive. Research projects that focus on various aging tissues or physiological systems, including skin and liver, cardiovascular, musculoskeletal, immune, urogenital, endocrine gastrointestinal and nervous systems, are of interest. Basic biology studies on aging that use animal models or human tissue are of interest. However, clinical studies in humans, beyond collection of tissues or cells for in vitro use, are outside the scope of this Program Announcement. A. Studies on individual tissues/organs: o Changes in adult stem cells and their environment that result in altered tissue and organ function with age. o Age-related changes in regulation of angiogenesis o The role of non-estrogen hormones and bio-regulatory factors separately or in combination with estrogen in the development of postmenopausal health problems related to particular tissues or organs o Mechanisms of age-related prostate growth in the adult. o Homeostatic mechanisms that regulate the size and composition of the T- cell pool and the naive and memory T-cell subsets with age. Mechanisms of attenuated function of the thymus and factors required to support normal T- cell differentiation and maturation. o Research to identify functionally important polymorphisms in genes that lead to changes in function of particular cells and tissues with age. Interactions among genes with particular polymorphisms that lead to greater or lesser change in function with age. o Basic biology research to understand gender and/or racial differences leading to altered rates or phenotype of change in tissues and organs with age. o Age-related changes in skin and wound healing o Age-related changes in steroid hormone levels and activity as well as activity of tissue-specific hormone-like compounds o Mechanisms of age-related change in the musculoskeletal system, including muscle atrophy, development of temporamandibular disorders (TMD), altered bone density, and development of osteoarthritis o Age-related changes in the regulation of neurogenesis o Mechanisms underlying age-related changes in cognition and in sleep, motor and sensory processes o Research on mechanisms controlling selective vulnerability of brain cells and circuits to atrophy and degeneration in normal aging and in neurodegenerative disorders o Identification and role of biological risk or protective factors, such as steroids, cytokines or neurotrophic factors, in modifying nervous system function in aging o Changes in gastrointestinal or hepatic function in aging o Age-related changes in insulin secretion and sensitivity and mechanisms underlying adipose tissue distribution and its metabolic effects B. Studies on aging changes affecting multiple tissues or organs: o Changes in cell numbers and function with age and how these changes affect function in multiple tissues and organs. Examples include membrane changes, cytoskeletal changes and cell signaling changes that have effects on function in multiple organs. o Effects of oxidative damage and mitochondrial dysfunction on aging of multiple organs and the tissues that constitute them. o Age-related changes in extracellular matrix and how these changes affect function in multiple tissues and organs. o Research to understand how decline in function of particular tissues with age relates to or causes decline in function of physically interacting tissues or organs. For example, how changes in articular cartilage affect underlying bone or how changes in the vascular system affect the brain. o Interactions between endocrine and/or immune system cells and factors and other organ systems and how changes in these interactions alter organ function with age. For example, how endocrine system changes affect cardiovascular or nervous system function, and how immune system changes affect inflammatory processes in the brain or may alter bone remodeling in the aged. MECHANISMS 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. This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see 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. ELIGIBLE INSTITUTIONS You may submit (an) application(s) 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 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 their institution to develop an application for support. Women, 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: Frank L. Bellino, Ph.D. Endocrinology Physiology National Institute on Aging 7201 Wisconsin Avenue, Suite 2C231 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: Jill L. Carrington, Ph.D. Chief, Systems Branch, Biology of Aging Program Musculoskeletal Biology National Institute on Aging 7201 Wisconsin Avenue, Suite 2C231 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: David B. Finkelstein, Ph.D. Cardiovascular Biology National Institute on Aging 7201 Wisconsin Avenue, Suite 2C231 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: Rebecca A. Fuldner, Ph.D. Immunology National Institute on Aging 7201 Wisconsin Avenue, Suite 2C231 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-6402 FAX: (301) 402-0010 Email: Stanley Slater, M.D. Geriatrics and Clinical Gerontology Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3E327 Bethesda, MD 20892-9205 Telephone: (301) 496-6761 FAX: (301) 402-1784 Email: Bradley C. 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: Lana Shekim, Ph.D. Scientific Programs Branch National Institute on Deafness and Other Communication Disorders 6120 Executive Blvd., Room 400C Bethesda, MD 20892-7180 Telephone: (301)-496-5061 Fax: (402)-402-6251 E-mail: Yasaman Shirazi, PhD Program Director, Epithelial Cell Regulation and Transformation Program Division of Basic & Translational Sciences National Institute of Dental & Craniofacial Research National Institutes of Health 45 Center Dr., Rm: 4AN-18C Bethesda, MD 20892-6402 Tel: 301-594-4812 Fax: 301-480-8318 Email: Kristin M. Abraham, Ph.D. Division of Diabetes, Endocrinology and Metabolic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 607, MSC 5460 Bethesda, MD 20892-5460 Telephone: (301) 451-8048 FAX: (301) 480-3503 E-mail: o Direct your questions about financial or grants management matters 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: Sara Stone Chief, Grants Management Branch National Institute on Deafness and Other Communication Disorders, 6120 Executive Blvd., Room 400B-MSC Bethesda, MD 20892-7180 Telephone: (301)-402-0909 Fax: (301)-402-1758 E-mail: Kevin Crist Grants Management Branch National Institute of Dental and Craniofacial Research Natcher Building, Room 4AN-44 45 Center Drive, MSC-6402 Bethesda, MD 20892-6402 Phone: (301) 594-4800 Fax: (301) 480-8303 Email: Randi Freundlich, R.D. Grants Management Specialist Division of Extramural Activities National Institute of Diabetes and Digestive and Kidney Diseases 6707 Democracy Boulevard, Rm. 714, MSC 5456 Bethesda, MD 20892-5456 Telephone: (301) 594-8825 FAX (301) 594-9523 E-mail: 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 in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at 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 includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at 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 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 institute program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study, 2) Obtain agreement from the institute staff that the institute will accept your application for consideration for award, and, 3) Identify, in a cover letter sent with the application, the staff member and institute that 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 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 received by or mailed on or before the receipt dates described at The 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 application must include an Introduction addressing the previous critique. 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 ( 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 the appropriate national advisory council or board 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, you 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 your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? 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? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your 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, your application will also be reviewed with respect to the following: PROTECTIONS: 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. INCLUSION: 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. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) 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 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 AMENDMENT "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 (, a complete copy of the updated Guidelines are available at 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. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy 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. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at 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 HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at and at Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. 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 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. 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 AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.866, 93.173, 93.121, 93.847, 93.848, and 93.849, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. 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 described at and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and 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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