RFA-AG-04-006: PROTEOMICS IN AGING AND AGE-RELATED DISORDERS

Department of Health
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PROTEOMICS IN AGING AND AGE-RELATED DISORDERS RELEASE DATE: October 07, 2003 RFA Number: RFA-AG-04-006 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATIONS: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATIONS: National Institute on Aging (NIA) (http://www.nia.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER(S): 93.866 LETTER OF INTENT RECEIPT DATE: January 23, 2004 APPLICATION RECEIPT DATE: February 23, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism(s) of Support o Funds Available o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Letter of Intent o Submitting an Application o Supplementary Instructions o Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA The National Institute on Aging (NIA) is soliciting applications that use proteomic approaches to study age-related changes in protein structure and function. Proteomics research is expected to provide significant insights into the cellular and molecular mechanisms of aging and age-associated disease processes. This Request for Applications (RFA) encourages projects that advance research to identify and quantitate protein expression patterns, post-translational modification of proteins, and protein-protein interactions which may change in cells or tissues as a direct result of the aging process or age-related pathology. Research projects that take advantage of various animal models of aging and of age-related human disease, and that focus on cells or tissues of aging physiological systems, such as the cardiovascular, musculoskeletal, immune, endocrine and nervous systems, are encouraged. RESEARCH OBJECTIVES Background The deciphering of whole genomes, both human and other species, allows for the identification of the entire complement of genes in a given species. However the genome is only the blueprint for the construction of cells and tissues, while the work of a cell is carried out primarily by proteins and other macromolecules. Proteomics is the study of the entire complement of proteins expressed in tissues, cells, and subcellular organelles, and their functional activities. Proteomics can build upon and extend large, genomic-scale gene expression studies by the global analysis of proteins using recently developed high throughput technologies. For example, protein microarrays have been used to analyze the activities of thousands of proteins and to examine protein interactions on a large scale in yeast. With the continued development of high throughput proteomics technology, dissection of the intricate mechanisms of cellular control, including protein stability, post-translational modifications such as phosphorylation, and the formation/dissociation of multi-protein complexes (subcellular machines), which may change with age, disease, and environmental conditions becomes a possibility. The purpose of this RFA is to utilize these emergent technologies to advance our understanding of the molecular mechanisms involved in aging and age-specific disease. Protein expression is a basic component of any proteomics endeavor related to aging. Analysis of the effect of aging on protein expression levels in subcellular organelles like mitochondria, in single or groups of cells, or in a tissue sample would provide key information about the cellular processes that occur during aging. Similar proteomics analysis of changes in protein expression in animal models of longevity or age- related neurodegenerative disorders would be informative about the underlying mechanisms contributing to the maintenance or decline of cell, tissue and organ function in normal or pathological aging. Ongoing advances in protein profiling methods for fixed tissue sections and in increasing the sensitivity and quantitation of low abundance proteins at the single cell level would be useful in the proteomic analysis of aging cells and tissues. Progress in genomics and microarray technologies have led to the concept that, while individual molecules might not be adequate markers for complex traits such as aging or age-related disease, panels of markers consisting of a defined subset of the molecules might serve as valuable predictors of these traits. In this context, changes in the proteome of different tissues or body fluids promises the possibility of identifying aging and age- related disease biomarkers. Of particular relevance to aging are protein modifications. Commonly observed changes in proteins with aging include: 1) Undesirable post- translational modifications, such as oxidation, glycation, aggregation, and changes in protein folding and degradation rates; and 2) Decreased ability to induce desirable modifications in response to external stimuli, as exemplified by decreased phosphorylation rate of signal transduction molecules. Proteomics presents a powerful way to identify the constellation of protein modifications leading to studies on the cellular mechanisms responsible for the changes. For example, protein oxidation in aging is an active area of research, and a global profile of oxidized proteins in cells or tissues should provide greater insight into the relevance of oxidative modification of proteins to aging or disease (e.g., Alzheimer's disease) processes, and into the action of "age-retarding" (e.g., dietary restriction) manipulations. Subsequent studies might then explore the extent of oxidative modification of specific proteins and its effect on protein activity. Research on other kinds of protein modifications and the biological significance of such modifications in aging and age-related disease is needed. Proteins typically are not present in isolation in cells, but rather interact with other proteins in a signaling pathway or as part of multi-protein complexes. Cellular receptors are often multi-protein complexes, the function of which requires the stable or transient interaction of membrane and intracellular proteins alike to form signaling complexes. Age-dependent subtle disruption of these interactions could have dramatic effects on cellular and tissue function and responsiveness to the external milieu. Isolation of protein complexes followed by mass spectrometry analysis has been and will continue to be a powerful method for describing networks of protein interactions and for unraveling the mechanisms of protein- protein interactions in response to stimuli and as a function of age and disease. Protein microarrays could be used for a proteome-wide analysis of protein activities and interactions as has been done in yeast. The challenge is to move the protein chip technology from the proteome of a simple organism to that of a more complex one. Protein structural or conformational changes brought about by oxidative or other modifications may also lead to abnormal (and often pathological) protein aggregation, which contributes to several well- known age-related pathologies, such as Alzheimer's disease or inclusion body myositis. Damaged, mutated or misfolded proteins are targeted for degradation by the ubiquitin-proteasome system or by lysosomes. Little is known about the composition and activity of the proteasome or molecular chaperones in aging or diseased cells and tissues. Proteomics research could provide further insights into the molecular mechanisms regulating protein aggregation and degradation in aging and how changes in these processes contribute to age-related disease. For example, proteomics approaches could be used to identify protein co- factors that modulate protein misfolding, to characterize the composition and dynamics of protein aggregates, and to characterize protein ubiquitination and other modifications involved in protein degradation which may change in cells or tissues as a result of the aging process. The Neuroscience and Neuropsychology of Aging Program and the Biology of Aging Program at the NIA encourage applications that use proteomics approaches to identify physiologically relevant changes in the proteome during aging or in the development of age-related disorders. Such an effort should help in furthering our understanding of both the molecular mechanisms behind these changes, and the physiological repercussions on the health of the individual. Such a global proteomic analysis is expected to provide significant insights into the cellular and molecular mechanisms of normal and pathological aging. The Biology of Aging Program supports research on tissue culture models, on lower organisms that serve as models of aging, and on most tissues and organs of the body outside of the nervous system, including the cardiovascular, musculoskeletal, endocrine, and immune systems. The Neuroscience and Neuropsychology of Aging Program supports research on the nervous system, including basic neurobiology, motor and sensory systems, integrative neurobiology, cognition and the dementias of aging, particularly Alzheimer's disease. Objectives and Scope The main objective of this RFA is to identify patterns of protein change in critical systems that dictate the loss of function of cells and tissues as a function of age and in age-related diseases. Use of, or modest enhancements to, existing techniques and validation of alternative available methods are encouraged. Age-related studies that use animal models or human tissue are of interest. However, clinical studies in humans, beyond collection of body fluids, tissues, or cells for in vitro analysis, are outside the scope of this RFA. Research proposals that focus on individual proteins (as opposed to full or partial proteome studies) also will not be considered responsive to this RFA. The examples below illustrate the types of research and experimental approaches that are of special interest, but these are only examples, and should not be considered as an exclusive list. o Analysis of global patterns of protein abundances and their changes during normal and pathological aging in various tissues, cells, or subcellular compartments. o Proteomic analysis of age-related changes in critical cellular pathways that form the basis for age-related changes in cell or tissue function. o Detection and quantification of patterns of post-translational protein modifications as a function of aging. o Proteomic approaches for analyzing protein aggregation and degradation during aging and their association with age-related disorders. o Proteomics-based analysis of age-related changes in protein-protein interactions and in the structure and function of multi-protein complexes. o Molecular imaging techniques to study age-related protein modification, localization, and interactions in cells or tissues. o Studies on the biological relevance and function of changes in protein quantity, modification and interactions in aging and age- specific disease, e.g., studies that directly link changes in the proteome with changes in organ function or animal behavior during aging. MECHANISM OF SUPPORT This RFA will use NIH research project grant (R01) and exploratory/developmental research grant (R21) award mechanisms. As an applicant you will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation. Future unsolicited, competing-continuation applications based on this project will compete with all investigator-initiated applications and will be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2004. Applications that are not funded in the competition described in this RFA may be resubmitted as NEW investigator-initiated applications using the standard receipt dates for NEW applications described in the instructions to the PHS 398 application. The R21 mechanism (see http://grants.nih.gov/grants/guide/pa-files/PA-03-107.html) is intended to encourage exploratory and developmental research projects by providing support for the early and conceptual stages of these projects. For example, such projects could assess the feasibility of a novel area of investigation or a new experimental system that has the potential to enhance health-related research. Another example could include the unique and innovative use of an existing methodology to explore a new scientific area. Applications for R21 awards should describe projects distinct from those supported through the traditional R01 mechanism. For example, long-term projects, or projects designed to increase knowledge in a well- established area will not be considered for R21 awards. Applications submitted under this mechanism should be exploratory and novel. These studies should break new ground or extend previous discoveries toward new directions or applications. This RFA uses just-in-time concepts. It also uses the modular budgeting format. (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 budget format. 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 The NIA intends to commit approximately $1.5 million in FY 2004 to fund 5 to 7 new grants in response to this RFA. An applicant may request a project period of up to 5 years and a budget for direct costs of up to $250,000 per year under the R01 mechanism. For an R21 grant application, an applicant may request a project period of up to two years and a combined budget for direct costs of up to $275,000 for the two year period, with no more than $200,000 being requested in any single year. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Although the financial plans of the NIA provide support for this program, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious 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 institutions/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 their 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. SPECIAL REQUIREMENTS Sharing of Unique Research Resources and Data: Restricted availability of unique research resources, upon which further studies are dependent, can impede the advancement of research. The NIH is interested in ensuring that particular research resources developed through grants become readily available to the broader research community in a timely manner for further research, development, and application, in the expectation that this will lead to products and knowledge of benefit to the public health. Data sharing promotes many goals of the NIH research endeavor. It is particularly important for unique data that cannot be readily replicated. Data sharing allows scientists to expedite the translation of research results into knowledge, products, and procedures to improve human health. The NIH endorses the sharing of final research data to serve these and other important scientific goals, and expects and supports the timely release and sharing of final research data from NIH supported studies for use by other researchers. Data should be made as widely and freely available as possible while safeguarding the privacy of participants, and protecting confidential and proprietary data. To address this interest in assuring that research data and resources are accessible NIH normally requires that applicants seeking $500,000 or more in direct costs in any single year submit a plan for data sharing. However, this RFA requires a data sharing plan for all applications for both the R01 and R21 mechanisms. NIA requires applicants who respond to this RFA to submit a plan (1) for sharing final research data generated through the grant or state why data sharing is not possible, (2) for sharing research resources generated through the grant, and (3) for exercising intellectual property rights, should any be generated through this grant, while making such research resources available to the broader scientific community. The data sharing plan should conform to NIH Data Sharing Policy in accordance with the Final NIH Statement on Sharing Research Data (http://grants.nih.gov/grants/guide/notice-files/NOT-OD-03-032.html). Guidance on NIH data sharing policy and implementation, including FAQs, is available at: http://grants.nih.gov/grants/policy/data_sharing/. The sharing of research resources plan and intellectual property plan must make unique research resources readily available for research purposes to qualified individuals within the scientific community in accordance with the NIH Grants Policy Statement (http://grants.nih.gov/grants/policy/nihgps_2001/) and the Principles and Guidelines for Recipients of NIH Research Grants and Contracts on Obtaining and Disseminating Biomedical Research Resources (http://www.ott.nih.gov/policy/rt_guide_final.html or http://ott.od.nih.gov/NewPages/64FR72090.pdf). Applicants are encouraged to discuss the plans with their Institutional Official and office of technology transfer prior to submission of the application. The applicant organization signature on the application indicates the agreement of the organization with the plan in the application. Annual Meeting of Investigators: It is the intent of the NIA to provide support for proteomics research by promoting collaboration and sharing of information among investigators on projects of interest to the NIA. Principal Investigators (PI) on grants resulting from this RFA must participate in annual meetings convened by the NIA to facilitate scientific interactions and information exchange among investigators and NIA program staff. Travel to this annual meeting, expected to be in Bethesda, MD, should be included in the budget request in the application. WHERE TO SEND INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues regarding projects focused on the nervous system to: Bradley C. Wise, Ph.D Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 350 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: wiseb@nia.nih.gov o Direct your questions about scientific/research issues regarding projects focused on non-neural tissues to: Felipe Sierra, 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: sierraf@nia.nih.gov o Direct your questions about peer review issues to: Mary Nekola, Ph.D. Chief, Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2C212 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9666 FAX: (301) 402-0066 Email: nekolam@nia.nih.gov o Direct your questions about financial or grants management matters to: Jeff Ball Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212 MSC 9205 Bethesda, MD 20892 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: ballj@nia.nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes the following information: o Descriptive title of the proposed research o Name, address, and telephone number of the Principal Investigator o Names of other key personnel o Participating institutions o Number and title of this RFA Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and plan the review. The letter of intent is to be sent by the date listed at the beginning of this document. The letter of intent should be sent to: Dr. Mary Nekola Chief, Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2C212 MSC 9205 Bethesda, MD 20892 Telephone: (301) 496-9666 FAX: (301) 402-0066 Email: nekolam@nia.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Applications must have a DUN and Bradstreet (D&B) Data Universal Numbering System (DUNS) number as the Universal Identifier when applying for Federal grants or cooperative agreements. The DUNS number can be obtained by calling (866) 705-5711 or through the web site at http://www.dunandbradstreet.com/. The DUNS number should be entered on line 11 of the face page of the PHS 398 form. The PHS 398 document is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 710-0267, Email: GrantsInfo@nih.gov. SUPPLEMENTARY INSTRUCTIONS: All instructions for the PHS 398 (rev. 5/2001) must be followed, with these exceptions: o Research Plan For R21 applications only, items a - d of the Research Plan (Specific Aims, Background and Significance, Preliminary Studies, and Research Design and Methods) may not exceed a total of 15 pages. No preliminary data is required for R21 proposals but may be included if it is available. Please note that a Progress Report is not needed for R21 awards; competing continuation applications for an exploratory/developmental grant will not be accepted. Appendix. Use the instructions for the appendix detailed in the PHS 398 except that for R21 applications no more than 5 manuscripts, previously accepted for publication, may be included. 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. USING THE RFA LABEL: The RFA label available in the PHS 398 (rev. 5/2001) application form must be affixed to the bottom of the face page of the application. Type the RFA number on the label. Failure to use this label could result in delayed processing of the application such that it may not reach the review committee in time for review. In addition, the RFA title and number must be typed on line 2 of the face page of the application form and the YES box must be marked. The RFA label is also available at: http://grants.nih.gov/grants/funding/phs398/labels.pdf. SENDING AN APPLICATION TO THE NIH: Submit a signed, typewritten original of the application, including the Checklist, and three 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) At the time of submission, two additional copies of the application and all copies of the appendix material must be sent to: Dr. Mary Nekola Chief, Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2C212 MSC 9205 Bethesda, MD 20892-9205 APPLICATION PROCESSING: Applications must be received on or before the application receipt date listed in the heading of this RFA. If an application is received after that date, it will be returned to the applicant without review. 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. 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. However, when a previously unfunded application, originally submitted as an investigator-initiated application, is to be submitted in response to an RFA, it is to be prepared as a NEW application. That is, the application for the RFA must not include an Introduction describing the changes and improvements made, and the text must not be marked to indicate the changes from the previous unfunded version of the application. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIA. Incomplete applications will not be reviewed. If the application is not responsive to the RFA, NIH 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 appropriate NIH review cycle. 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: o Undergo a process in which only those applications deemed to have the highest scientific merit, generally the top half of the applications under review, will be discussed and assigned a priority score o Receive a written critique o 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 evaluate the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. The scientific review group will address and consider each of the following criteria in assigning the application's overall score, weighting them as appropriate for each application. o Significance o Approach o Innovation o Investigator o Environment 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. 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 AND MINORITIES IN RESEARCH: The adequacy of plans to include subjects from both genders, and all racial and ethnic groups (and subgroups), as appropriate for the scientific goals of the research. 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 REVIEW CONSIDERATIONS Sharing Research Data and Resources: Reviewers will comment, as appropriate, on the adequacy and feasibility of the sharing of research resources and intellectual property plans. The reasonableness of the data sharing plan or the rationale for not sharing research data also will be assessed by the reviewers. However, reviewers will not factor the proposed research resources and data sharing plans into the determination of scientific merit or priority score. Comments on the plans and any concerns will be presented in an administrative note in the Summary Statement. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: January 23, 2004 Application Receipt Date: February 23, 2004 Peer Review Date: June 2004 Council Review: August 2004 Earliest Anticipated Start Date: September 1, 2004 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review) o Availability of funds o Programmatic 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 SHARING RESEARCH DATA: Starting with the October 1, 2003 receipt date, investigators submitting an NIH application seeking more than $500,000 or more in direct costs in any single year are expected to include a plan for data sharing or state why this is not possible. http://grants.nih.gov/grants/policy/data_sharing Investigators should seek guidance from their institutions, on issues related to institutional policies, local IRB rules, as well as local, state and Federal laws and regulations, including the Privacy Rule. Reviewers will consider the data sharing plan but will not factor the plan into the determination of the scientific merit or the priority score. 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 are 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. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://stemcells.nih.gov/index.asp and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide, in the project description and elsewhere in the application as appropriate 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 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 RFA is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.healthypeople.gov/. 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 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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