STEM CELL PLASTICITY IN HEMATOPOIETIC AND NON-HEMATOPOIETIC TISSUE Release Date: November 13, 2000 RFA: HL-01-007 National Heart, Lung, and Blood Institute http://www.nhlbi.nih.gov National Institute of Diabetes and Digestive and Kidney Diseases http://www.niddk.nih.gov National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov Letter of Intent Receipt Date: February 6, 2001 Application Receipt Date: March 12, 2001 THIS RFA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS RFA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS RFA. PURPOSE The Cellular Hematology Scientific Research Group, Division of Blood Diseases and Resources, NHLBI, the Hematology Program, Division of Kidney, Urologic, and Hematologic Diseases, NIDDK, and the Repair and Plasticity Program, NINDS announce the availability of a Request for Applications (RFA) on the above subject. The objective of this initiative is to promote the thorough exploration and characterization of stem cell plasticity in hematopoietic and non-hematopoietic tissue. Research efforts are needed to test stem cell plasticity in a rigorous manner. It is of particular importance to characterize cellular and molecular mechanisms that lead to the capacity of adult stem cells with hematopoietic potential to express other potentials and precursor cells of adult non-hematopoietic tissues to express hematopoietic potential. Other areas of high interest include the ability of stem cells from non-neuronal tissues to differentiate along neuronal and glial lineages. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as Principal Investigators. Domestic applications may include foreign components. FOREIGN INSTITUTIONS: Awards under this announcement may be made to foreign institutions provided the application (1) is of high scientific merit and (2) offers a special opportunity for furthering research programs through the use of unusual talents, resources, populations, or conditions in other countries which are not readily available in the United States or which augment existing U.S. resources. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded under this RFA. 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 Request for Applications (RFA), "Stem Cell Plasticity in Hematopoietic and Non-Hematopoietic Tissue" is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2010" at http://www.health.gov/healthypeople/ MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) individual research project grant (R01) mechanism of support. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed four (4) years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is September 30, 2001. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at https://grants.nih.gov/grants/funding/modular/modular.htm For this RFA, funds must be requested in $25,000 direct cost modules and a maximum of ten modules ($250,000 direct costs) per year may be requested. Only limited budget information will be required and any budget adjustments made by the Initial Review Group will be in modules of $25,000. The APPLICATION PROCEDURES section of this RFA provides specific details of modifications to standard PHS 398 application kit instructions. Applicants, who will plan and execute their own research programs, are requested to furnish their own estimates of the time required to achieve the objectives of the proposed research project. Up to four years of support may be requested. At the end of the official award period, renewal applications may be submitted for peer review and competition for support through the regular grant program of the sponsoring Institutes. It is anticipated that support for the present program will begin September 30, 2001. Administrative adjustments in project period or amount of support may be required at the time of the award. All current policies and requirements that govern the research grant programs of the NIH will apply to grants awarded in connection with this RFA. FUNDS AVAILABLE The three sponsoring Institutes intend to commit approximately $2,000,000 each for total costs for the first year of support (totaling $6,000,000)in FY 2001 to fund twelve to eighteen new grants submitted in response to this RFA. An applicant may request a project period of up to four years and a budget for direct costs of up to $250,000 (ten modules of $25,000). Facilities and administrative costs will be awarded based on the negotiated rates. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of the sponsoring Institutes is to 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. At this time, it is not known if this RFA will be reissued. Although not formally participating in this request for applications, the National Institute on Aging is interested in research on the plasticity of stem cells from hematopoietic and non-hematopoietic tissue in generating neuronal, astroglial and microglial cells of the nervous system. Also, the National Cancer Institute has an evolving interest in the application of pluripotent stem cell technologies to cancer therapy and the understanding of the etiology of malignant disease. RESEARCH OBJECTIVES Background Stem cell research offers enormous potential for treating devastating malignant and non-malignant diseases. Recently, a number of groups have reported that stem cells derived from adults may be capable of surprising plasticity or versatility. Investigators reported that after bone marrow transplantation, donor-derived cells could be found in non-hematopoietic tissues. These tissues included astroglia in the central nervous system, skeletal muscle, liver oval cells, cardiomyocytes, vascular-endothelial cells, and bone forming osteoblasts. In addition, bone marrow stromal cells from rats and humans can apparently give rise to large numbers of cells with neuronal properties under specific culture conditions. Also, muscle derived material was reported to display hematopoietic activity. In these studies, diagnostic cell surface markers have shown the reconstitution of both myeloid and lymphoid cell lineages after transplantation. Neuronal cells have also been reported to give rise to progenitors of all blood lineages and to demonstrate myogenic potential. Thus, increasing evidence suggests that adult cells could have far greater differentiative plasticity even at advanced stages of their differentiation programs than previously thought. The plasticity concept resembles the documented phenomenon known as transdifferentiation. However, the extent to which the transdifferentiation principle can be generalized to current findings is unknown. Findings such as those described above raise many unanswered and intriguing questions regarding the biology of stem cells and the routes they take to express their differentiation potential. This RFA is developed to encourage research to substantiate stem cell plasticity and to characterize cellular, molecular, and genetic mechanisms that allow cells to express plasticity. The National Heart, Lung, and Blood Institute sponsored a meeting entitled, "Working Group on Stem Cell Plasticity" in March, 2000 to assess the state-of- science in this area. The final report is located at http://www.nhlbi.nih.gov/meetings/scplast.htm For the purpose of this announcement, plasticity is defined to mean either (1) non-hematopoietic lineage potential in hematopoietic stem cells or (2) hematopoietic potential in stem cells of other systems. It is acknowledged that cells from different tissue sources may have different potentials. Rigorous studies which establish and address the breadth of plasticity and its physiological relevance, and the molecular and cellular requirements to reveal plasticity including the identification of necessary stem/progenitor cell markers, timing, and microenvironmental cues, are important research areas to pursue. This initiative is particularly directed to the use of well-defined, in vivo systems to assess stem cell plasticity, such as those established for the study of hematopoietic stem cells or for region-specific differentiation and integration into the nervous system. In addition, projects exploring potential hematopoietic or neuronal repertoires of mesenchymal precursor cells would be directly relevant to this RFA. However, studies which focus on stem cell expansion or differentiation within a given tissue (e.g., hematopoietic stem cell expansion with cytokines, signals required for differentiation of neurons from neuronal stem cells) are not responsive. In addition, basic and developmental mesenchymal cell biology projects are not responsive to this RFA. Examples of research needs are identified below. o Rigorous testing for stem cell plasticity through application of clonal approaches (e.g., micro-manipulation of single cells, limiting dilution analyses, retroviral insertion marking, etc.) o Determine whether individual cells with hematopoietic potential can express other potentials. o Determine whether individual cells with other potentials (muscle, CNS, etc.) in other sites of the body also have hematopoietic potentials. o Conduct comparative studies between adult somatic cells with pluripotential properties with the aim of defining a rigorous phenotype for somatic stem cells from specific tissues. Also, comparative studies between somatic stem cells and embryonic stem cells to identify the extent that individual primary and ES cells share properties are of interest. o Examine the mechanisms of trafficking, homing, engraftment, and integration of stem cells in the host with the emphasis on the capability of cells derived from one tissue to engraft into another. o Develop novel approaches to manipulate transplantable cells and/or the host in order to facilitate production of desired cell types for stem cell transplantation. o Develop clinically relevant small and large animal models to make use of the concept of stem cell plasticity. The above examples of research approaches are not meant to be all inclusive or restrictive. Prospective applicants are encouraged to develop their own ideas of research on which to address the goals of the RFA. SPECIAL REQUIREMENTS Upon initiation of the program, sponsoring Institutes will arrange annual meetings to encourage the exchange of information among investigators who participate in this program. In the preparation of the budget for the grant application, applicants should include travel funds for one meeting each year to be held in Bethesda, Maryland. Applicants should also include a statement in the applications indicating their willingness to participate in such meetings. This initiative is particularly directed to the use of well-defined, in vivo systems to assess stem cell plasticity (for the purpose of this announcement see definition above) such as those established for the study of hematopoietic stem cells or for region-specific differentiation and integration into the nervous system. In addition, projects exploring potential hematopoietic or neuronal repertoires of mesenchymal precursor cells would be directly relevant to this RFA. However, studies which focus on stem cell expansion or differentiation within a given tissue (e.g., hematopoietic stem cell expansion with cytokines, signals required for differentiation of neurons from neuronal stem cells) are not responsive. In addition, basic and developmental mesenchymal cell biology projects are not responsive to this RFA. GUIDELINES FOR RESEARCH USING HUMAN PLURIPOTENT STEM CELLS All investigators proposing research using human pluripotent stem cells should read the National Institutes of Health Guidelines for Research Using Human Pluripotent Stem Cells (the Guidelines) published in the Federal Register on August 25, 2000 and is available at the following URL address: http://stemcells.nih.gov/news/newsArchives/fr25au00-136.asp Details on the approval process and the procedures for submitting the required documentation of compliance are at the following URL address: https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-050.html INCLUSION OF WOMEN AND MINORITIES IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification are 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 research involving human subjects should read the UPDATED "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research," published in the NIH Guide for Grants and Contracts on August 2, 2000 https://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-048.html A complete copy of the updated Guidelines are available at https://grants.nih.gov/grants/funding/women_min/guidelines_update.htm. The revisions relate to NIH defined Phase III clinical trials and require: a) all applications or proposals and/or protocols to 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) all investigators to report accrual, and to conduct and report analyses, as appropriate, by sex/gender and/or racial/ethnic group differences. INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. 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 was published in the NIH Guide for Grants and Contracts, March 6, 1998, and is available at the following URL address: https://grants.nih.gov/grants/guide/notice-files/not98-024.html. Investigators also may obtain copies of these policies from the program staff listed under INQUIRIES. Program staff may also provide additional relevant information concerning the policy. 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. Reviewers are cautioned that their anonymity may be compromised when they directly access an Internet site. LETTER OF INTENT Prospective applications are asked to submit, by February 6, 2001, a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows staff to estimate the potential review workload and to plan the review. The letter of intent is to be mailed, or faxed, to Dr. Deborah Beebe at the address listed under INQUIRIES. APPLICATION PROCEDURES The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research and from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. The modular grant concept establishes specific modules in which direct costs may be requested as well as a maximum level for requested budgets. Only limited budgetary information is required under this approach. The just-in-time concept allows applicants to submit certain information only when there is a possibility for an award. It is anticipated that these changes will reduce the administrative burden for the applicants, reviewers and Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See https://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: https://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. Applications not conforming to these guidelines will be considered unresponsive to this RFA and will be returned without further review. Applicants from institutions that have a General Clinical Research Center (GCRC) funded by the NIH National Center for Research Resources may wish to identify the GCRC as a resource for conducting the proposed research. If so, a letter of agreement from either the GCRC program director or principal investigator could be included with the application. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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 sample RFA label available at: https://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. 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 must be sent to Dr. Deborah Beebe at the address listed under INQUIRIES. Applications must be received by the application receipt date listed in the heading of this RFA (MARCH 12, 2001). If an application is received after that date, it will be returned to the applicant without review. The Center for Scientific Review (CSR) will not accept any application in response to this RFA that is essentially the same as one currently pending initial review, unless the applicant withdraws the pending application. The CSR will not accept any application that is essentially the same as one already reviewed. This does not preclude the submission of substantial revisions of applications already reviewed, but such applications must include an introduction addressing the previous critique. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the sponsoring Institutes staff. Incomplete and/or non- responsive applications will be returned to the applicant without further consideration. Studies which focus on stem cell expansion or differentiation within a given tissue (e.g., hematopoietic stem cell expansion with cytokines, signals required for differentiation of neurons from neuronal stem cells) are not responsive to this RFA. In addition, basic and developmental mesenchymal cell biology projects are not responsive. 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 NHLBI in accordance with the review criteria stated below. As part of the initial merit review, all applications will receive a written critique and 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, assigned a priority score, and 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 the application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals. Each of these criteria will be addressed and considered in assigning the overall score, weighting them as appropriate for each application. Note that the application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, an investigator may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) 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? (2) 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? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) 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)? (5) 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? In addition to the above criteria, in accordance with NIH policy, all applications will also be reviewed with respect to the following: o The adequacy of plans to include both genders, minorities and their subgroups, and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. o The reasonableness of the proposed budget and duration in relation to the proposed research. o 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. AWARD CRITERIA The anticipated date of award is September 30, 2001. Funding decisions will be made on the basis of scientific and technical merit as determined by peer review, program needs and balance, and the availability of funds. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or answer questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Dr. Helena O. Mishoe Division of Blood Diseases and Resources National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 10156 Bethesda, MD 20892-7950 Telephone: (301) 435-0050 FAX: (301) 480-0868 Email: Mishoeh@nih.gov Dr. David G. Badman Division of Kidney, Urologic, and Hematologic Diseases National Institute of Diabetes and Digestive and Kidney Diseases 2 Democracy Plaza, Room 621 MSC 5458 6707 Democracy Blvd. Bethesda, MD 20892-5458 Telephone: (301) 594-7717 FAX: (301) 480-3510 Email: Badmand@extra.niddk.nih.gov Dr. Arlene Y. Chiu Repair and Plasticity Program National Institute of Neurological Disorders and Stroke 6001 Executive Blvd., Room 2206, MSC 9525 Bethesda, MD. 20892-9525 Telephone: (301) 496-1447 FAX: (301) 480-1080 Email: chiua@ninds.nih.gov Direct inquiries regarding review issues, send letter of intent and two copies of the application to: Dr. Deborah Beebe Chief, Review Branch Division of Extramural Activities National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7178, MSC 7924 Bethesda, MD 20892-7924 (20817 for express mail) Telephone: (301) 435-0270 FAX: (301) 480-3541 Email: BeebeD@nhlbi.nih.gov Direct inquiries regarding fiscal matters to: Ms. Suzanne White Grants Management Office National Heart, Lung, and Blood Institute 6701 Rockledge Drive, MSC 7926 Bethesda, MD 20892-7926 Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: sw52h@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.839, 93.848, and 93.854. 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 and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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