RFA-AG-04-009: ASSAYS OF STEM CELL FUNCTION IN CLINICAL AGING RESEARCH

Department of Health
and Human Services (HHS)

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ASSAYS OF STEM CELL FUNCTION IN CLINICAL AGING RESEARCH RELEASE DATE: October 28, 2003 RFA Number: RFA-AG-04-009 Department of Health and Human Services (DHHS) PARTICIPATING ORGANIZATION: National Institutes of Health (NIH) (http://www.nih.gov) COMPONENTS OF PARTICIPATING ORGANIZATION: National Institute on Aging (NIA) (http://www.nia.nih.gov) CATALOG OF FEDERAL DOMESTIC ASSISTANCE NUMBER: 93.866 LETTER OF INTENT RECEIPT DATE: December 19, 2003 APPLICATION RECEIPT DATE: January 21, 2004 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanisms 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 Peer Review Process o Review Criteria o Receipt and Review Schedule o Award Criteria o Required Federal Citations PURPOSE OF THIS RFA This Request for Applications (RFA) is to solicit proposals for: a) clinical and epidemiologic studies to increase knowledge about the role in humans of stem cell deficits, and of variation in stem cell numbers and function, on health and functional outcomes in old age, and on age- related physiologic changes and progression of chronic diseases, and/or b) research to develop or improve assays of human stem cell number and/or function that could be used in the types of studies indicated above. RESEARCH OBJECTIVES As knowledge of stem cell biology increases, it enhances prospects to develop and apply assays of stem cell number and function that could be used in clinical and epidemiologic aging studies to examine the role in humans of stem cell deficits, and of variation in stem cell numbers and function, on health and functional outcomes in old age, and on age- related physiologic changes and progression of chronic diseases. Such assays may also be useful in evaluating response to stem cell interventions, or other interventions that may alter stem cell number or function. There has been progress in development of assays of stem cell number and function in a variety of lineage for bone, blood, muscle, fat, and cardiovascular tissues, but more research on the validity and reliability of assays, and on development of new assays, is needed for these and other tissues to realize the full potential for clinical and epidemiologic aging research applications of measures of stem cell number and function. This RFA invites applications for research in two general areas: 1. For assays that are sufficiently reliable, valid, and feasible for clinical interventions or epidemiologic aging research, applications are invited for projects to: o Evaluate the role of age-related stem and progenitor cell deficits as risk factors for age related conditions. In addition, effects on age- related physiologic changes such as alterations in body composition, and on functional problems such as impaired responses to injury, infections, chemotherapy, ischemic damage, or other stressors are of interest. o Determine long-term effects of variation in stem cell number or function within the normal range during old age or earlier in life, on health outcomes in old age. (E.g., retrospective studies using stored blood or tissue samples.) o Determine effects of factors that influence rates of change with age in human stem cell populations, and their relationships to health outcomes o Evaluate interventions that might influence endogenous stem cell production, survival, or function in older persons, and potential age- related differences inefficacy or adverse effects of such interventions. o Determine effects of variation in stem cell number or function in old age on responses to therapeutic or preventive interventions (e.g., hormonal, pharmacologic, or surgical interventions, and immunization. 2. For stem cell types of interest with regard to the above questions, for which satisfactory assays for clinical and epidemiologic aging research purposes have not yet been developed, proposals are invited for research to determine and/or improve the validity, reliability, and feasibility of assays of numbers and/or function of specific stem cell types. The following topics are of particular interest: o To improve validity of assays, more information is needed on the relationship of specific markers to specific functional human cell phenotypes. The potential gains in validity of approaches using multiple markers to characterize stem cell populations also need to be tested. o More information is needed on the reliability of human stem cell assays with regard to characteristics such as within-subject variation, and differences in results from sampling from different tissue sites. Research on strategies to improve reliability of assays is also encouraged. o Given limitations on the amount of tissue available from biopsy or other human tissue samples, particularly from healthy volunteers, research is needed on development and validation of approaches for clinical and epidemiologic studies that can be performed with small samples. o Validation and determination of reliability of assays for various circulating progenitor populations in blood. This is especially important in regard to possibilities for larger-scale studies with more frequent and/or long-term sampling to validate and apply assays of specific circulating progenitor cell function. The potential for sampling over longer periods is especially important for prospective clinical and epidemiologic aging studies, since outcomes may be many years removed from age-related changes in stem cell populations. o Improvement, development, and validation of in vitro methods to assay human stem cell number or function that reflect individual differences among cell or tissue donors. Proposals for assay validation or development in the above areas should include, in the rationale for the proposed study, a description of the particular clinical and/or epidemiologic aging research question(s) that could be addressed better through the use of the assays to be developed or validated. Two topics of particular interest regarding both clinical and epidemiologic studies using available assays, and the development of new assays, are: o Age-related changes in the distribution of early precursor stages in lineages from more differentiated ones, and the potential clinical and functional consequences of such changes. o Potential systemic effects of age-related alterations in stem and precursor cell properties in specific lineages, beyond their consequences for their specific tissue (e.g., effects on other tissues of cytokines or other circulating factors produced by the stem cells). Potential applicants interested in conducting basic research on the role of stem cells in tissue maintenance and disease in aging are encouraged to review the companion NIA RFA AG-04-008 Biology of Stem Cells in Aging. The full text of this RFA can be found on the NIA website for Current Funding Opportunities at: http://www.nia.nih.gov/data/fundbrowse.asp. MECHANISMS OF SUPPORT This RFA will use NIH R01 and 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. This RFA uses just-in-time concepts. It also uses the modular budgeting format (see http://grants.nih.gov/grants/funding/modular/modular.htm). 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 approximately $1.5 million in FY 2004 to fund 5 to 6 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. 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. R21 applications for Exploratory/Developmental Research grants may request up to two years of support with a combined budget for direct costs of up to $275,000 for the two year period. For example, the applicant may request $100,000 in the first year and $175,000 in the second year. The request should be tailored to the needs of the project. Normally, no more than $200,000 may be requested in any single year. Exploratory/Developmental grant support is for new project only; competing continuation applications will not be accepted for this mechanism. 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 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 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 It is the intent of the NIA to provide support for stem cell research through grant support and through promoting collaboration and information sharing between investigators on projects of interest to the NIA. Principal Investigators (PI) on grants resulting from this RFA must participate in an annual workshop as convened by the NIA for updates and exchange of information related to the projects supported by these grants. In the event the PI is unable to attend, a mutually acceptable designee may be agreed upon by the PI and NIA staff to participate. Travel to this annual workshop, 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 to: Chhanda Dutta, Ph.D. Geriatrics and Clinical Gerontology Program National Institute on Aging 7201 Wisconsin Avenue, Room 3C307 MSC 9205 Bethesda, MD 20892-9205 Telephone: 301-435-3048 E-mail: cd23z@nih.gov o Direct your questions about peer review issues to: Mary Nekola, Ph.D. Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Room 2C212 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9666 Email: nekolam@nia.nih.gov o Direct your questions about financial or grants management matters to: Cynthia Riddick Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue Suite 2N212 MSC 9205 Bethesda, MD 20892 Telephone: (301) 496-1472 Email: riddickc@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: Mary Nekola, Ph.D. Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Room 2C212 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9666 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. 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: Mary Nekola, Ph.D. Scientific Review Office National Institute on Aging 7201 Wisconsin Avenue, Room 2C212 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9666 Email: nekolam@nia.nih.gov 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 (IC). Incomplete and/or nonresponsive applications will not be reviewed. 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. 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: December 19, 2003 Application Receipt Date: January 21, 2004 Peer Review Date: June 2004 Council Review: September 2004 Earliest Anticipated Start Date: September 30, 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 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 RFA 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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