NIH Guide: BASIC RESEARCH ON MESENCHYMAL STEM CELL BIOLOGY

BASIC RESEARCH ON MESENCHYMAL STEM CELL BIOLOGY RELEASE DATE: March 6, 2002 RFA: HL-02-018 National Heart, Lung and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov)National Institute on Aging (NIA) (http://www.nia.nih.gov) LETTER OF INTENT RECEIPT DATE: May 15, 2002 APPLICATION RECEIPT DATE: June 20, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATIONo Purpose of this RFAo Research Objectiveso Mechanism of Support o Funds Availableo Eligible Institutionso Individuals Eligible to Become Principal Investigatorso Special Requirementso Where to Send Inquirieso Letter of Intento Submitting an Applicationo Peer Review Processo Review Criteriao Receipt and Review Scheduleo Award Criteriao Required Federal Citations:PURPOSE OF THIS RFA Preclinical studies suggest mesenchymal stem cells facilitate hematopoietic stem cell transplantation while decreasing immune rejection of allogeneic transplants. In addition, mesenchymal stem cells have been demonstrated to differentiate into a variety of non-hematopoietic tissues including bone, cartilage, tendon, fat, skeletal and cardiac muscle, and early progenitors of neural cells. The National Heart, Lung and Blood Institute and National Institute on Aging invite applications on basic research on mesenchymal stem cell biology that will provide the basis for clinical application to hematopoietic and non-hematopoietic stem cell transplantation. RESEARCH OBJECTIVESBackgroundMesenchymal stem cells are pluripotent progenitor cells located in bone marrow that can differentiate into a variety of non-hematopoietic tissues including bone, cartilage, tendon, fat, muscle, and early progenitors of neural cells. However, mesenchymal stem cells have not been shown to produce blood cells. Preclinical and early clinical safety studies are paving the way for further applications of these cells in the field of transplantation with respect to hematopoietic support, immunoregulation, graft facilitation, and potentially gene therapy. Preclinical studies suggest mesenchymal stem cells may enhance the ability of the bone marrow microenviornment to support hematopoiesis after stem cell transplantation. Moreover, an important role in immunoregulation is suggested by reports that these cells can suppress T cell activation without inducing allogeneic anergy. These findings may have important applications for stem cell transplantation, organ transplantation, and other regenerative and reparative therapies.ScopeThe therapeutic implication of these studies for hematopoietic and non-hematopoietic stem cell transplantation is tremendous. However, the ability to identify the most appropriate population and assay methods that characterize the clinical potential of candidate human mesenchymal stem cells are currently lacking. Isolation and characterization standards would permit the comparison of results and this would significantly enhance multi-disciplinary, collaborative approaches to these important problems. Studies in this area will help ensure that future clinical protocols will be based on a solid foundation of basic science. The scope of this RFA also includes applications that address the undefined lineage relationship of hematopoietic and mesenchymal stem cells. In addition, comparative studies of mesenchymal stem cells and postnatal stem cells are also encouraged. However, the scope of the RFA is not limited to the areas defined above and research applications addressing other important areas of mesenchymal cell biology are encouraged.Examples of research areas of interest: o Basic mesenchymal stem cell biology.o Studies defining the lineage relationship between mesenchymal stem cells and other stem cells.o Novel markers for mesenchymal stem cell identification to enhance isolation and purification and to facilitate ex vivo stem cell expansion systems.o Refinement of cellular culture systems and elucidation of the molecularevents that permit ex vivo expansion of mesenchymal stem cells.o Identification and characterization of functional, molecular regulators ofmesenchymal stem cell self-renewal and commitment.o In vivo and in vitro assay systems for human mesenchymal stem cells.o Role of growth factors, cytokines, receptors, transmembrane signaling,marrow microenvironment, and adhesive proteins in mesenchymal stem cell interactions and hematopoiesis.o Identification and characterization of mechanisms by which mesenchymal stem cells increase stem cell engraftment.o Histocompatibility and allo-interactions, mechanism of induction oftransplant tolerance, minimizing the graft vs. host effect and graft rejection for organ and cellular transplants of heart, lung, or blood tissues.o Studies on the biology of mesenchymal stem cells in aging including changes in potential, population dynamics, mobilization, and interaction with the aging environment.o Basic research studies to develop future mesenchymal stem cell therapies to correct genetic diseases or for repair or regeneration of tissue or organ damage.o Basic research studies to develop future gene therapy approaches using mesenchymal stem cells as targets for gene insertion and long-term expression of normal genes using viral and non-viral approaches to gene transduction. MECHANISM OF SUPPORT This RFA will use NIH R01 award mechanism. 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 April 1, 2003.This RFA uses just-in-time concepts. It also uses the modular budgeting format. (see http://grants.nih.gov/grants/funding/modular/modular.htm). FUNDS AVAILABLE The two participating Institutes intends to commit approximately $ 2,400,000 to fund 5 to 6 new competitive grants 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 per 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 sponsoring Institutes 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. 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 governmentso Eligible agencies of the Federal government o Domestic or foreignINDIVIDUALS 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 REQUIREMENTSANNUAL INVESTIGATOR MEETINGS: Upon initiation of the program, the NHLBI and NIA will sponsor joint annual meetings to encourage the exchange of information among investigators who participate in this program, perhaps in conjunction with other Institute sponsored stem cell programs. In the preparation of the budget for the grant application, applicants should Include travel funds for the 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.WHERE TO SEND INQUIRIESWe encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or
grants management issues:o Direct your questions about scientific/research issues to:Dr. John W. ThomasDivision of Blood Diseases and ResourcesNational Heart, Lung, and Blood InstituteTwo Rockledge Centre, Room 101546701 Rockledge DriveBethesda, MD 20892-7950Telephone: (301) 435-0050FAX: (301) 451-5453Email: ThomasJ@nhlbi.nih.gov Dr. Jill L. CarringtonBiology of Aging ProgramNational Institute on Aging7201 Wisconsin Avenue Suite 2C231Bethesda, MD 20892Telephone: (301) 496-6402FAX: (301) 402-0010Email: CarringtonJ@nia.nih.gov o Direct your questions about financial or grants management matters to:Suzanne WhiteNational Heart, Lung, and Blood Institute6701 Rockledge Drive / Room 7154 / Mail Stop 7926Bethesda, MD 20817-7926Telephone: (301) 435-0171FAX: (301) 480-3310Email: WhiteSA@nhlbi.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 researcho Name, address, and telephone number of the Principal Investigatoro Names of other key personnel o Participating institutionso 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:Anne P. Clark, Ph.D.Division of Extramural AffairsNational Heart, Lung, and Blood Institute6701 Rockledge Drive, Room 7178 (MSC 7924)Bethesda, MD 20892-7924 (20817 for Courier)Telephone: (301) 435-0270Fax: (301) 480-0730Email: ClarkA@nhlbi.nih.gov SUBMITTING AN APPLICATIONApplications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. 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/label-bk.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 ReviewNational Institutes Of Health6701 Rockledge Drive, Room 1040, MSC 7710Bethesda, MD 20892-7710Bethesda, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application as well as all five collated sets of Appendix material must be sent to: Anne P. Clark, Ph.D.Division of Extramural AffairsNational Heart, Lung, and Blood Institute6701 Rockledge Drive, Room 7178 (MSC 7924)Bethesda, MD 20892-7924 (20817 for Courier)Telephone: (301) 435-0270Fax: (301) 480-0730Email: ClarkA@nhlbi.nih.gov APPLICATION PROCESSING: Applications must be received by 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. 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.Principal investigators should not sent supplementary material without first contacting the Scientific Review Administrator (SRA). The SRA will be identified in the letter sent to you indicating that your application has been received. If you have not received such a letter within three weeks after submitting the application, contact Dr. Anne Clark at the address listed under Submitting an Application.PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NHLBI and NIA. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration.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:o Receive a written critiqueo 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 scoreo Receive a second level review by the Heart, Lung and Blood National Advisory Council or the National Advisory Council on Aging. REVIEW CRITERIAThe goals of NIH-supported research are to advance our understanding of biological systems, improve the control of disease, and enhance health. In the written comments, reviewers will be asked to discuss the following aspects of your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovationo Investigatoro Environment The scientific review group will address and consider each of these criteria in assigning your application's overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward.(1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field?(2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics?(3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies?(4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)?(5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evi
dence of institutional support?ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following:o PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application.o INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated.o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research.RECEIPT AND REVIEW SCHEDULELetter of Intent Receipt Date: May 15, 2002Application Receipt Date: June 20, 2002Peer Review Date: October/November 2002Council Review: February 6-7, 2003Earliest Anticipated Start Date: April 1, 2003AWARD CRITERIAAward criteria that will be used to make award decisions include:o Scientific merit (as determined by peer review)o Availability of fundso Programmatic priorities. REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43).All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (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.INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998.All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. 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://grants.nih.gov/grants/stem_cells.htm 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 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.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.health.gov/healthypeople.AUTHORITY AND REGULATIONS: This program is described in the Catalog of Federal Domestic Assistance No. 93.839 and 93.866, and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-2
27, 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.http://grants.nih.gov/grants/guide/pa-files/PA-02-015.html.

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NIH Guide: BASIC RESEARCH ON MESENCHYMAL STEM CELL BIOLOGY