EXPLORATORY CENTER GRANTS FOR HUMAN EMBRYONIC STEM CELL RESEARCH RELEASE DATE: October 16, 2002 RFA: GM-03-003 (see re-announcement RFA-GM-05-004) National Institute of General Medical Sciences (NIGMS) (http://www.nigms.nih.gov) LETTER OF INTENT RECEIPT DATE: February 13, 2003; standard time limit for P20s APPLICATION RECEIPT DATE: March 13, 2003 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 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 of General Medical Sciences (NIGMS) invites applications for P20 Exploratory Grants that will support multi- investigator teams to conduct research using human embryonic stem cells (HESC). The purpose of this RFA is to encourage and enable basic biologists with little or no prior HESC experience to work with HESC and establish the utility of HESC as a model system by: 1) supporting the development of an institutional infrastructure for research using HESC; 2) encouraging research on the growth and maintenance requirements of HESC; 3) identifying biochemical and molecular markers of HESC; 4) stimulating research that will lead to a better understanding of the unique properties of HESC; and 5) supporting pilot projects that exploit the advantages of HESC as a model system to further the study of fundamental research problems. The source of HESC will be limited to federally approved stem cell lines listed on the NIH Human Embryonic Stem Cell Registry, which can be found at http://escr.nih.gov. RESEARCH OBJECTIVES Background On August 9, 2001, President Bush announced his decision to allow Federal funds to be used for research on existing human embryonic stem cell lines. Subsequently, the NIH Human Embryonic Stem Cell Registry was created to provide a listing of federally approved Human Embryonic Stem Cell Lines http://escr.nih.gov that may be used for such research. The availability of HESC for federally funded research affords a unique opportunity for investigators to use these cells to address fundamental research questions. However, most institutions and investigators have little or no prior experience in growing and maintaining HESC and remarkably little is known about the molecular and genetic properties of HESC that distinguish them from more differentiated cells. Therefore, NIGMS hosted a workshop on the Basic Biology of Mammalian Stem Cells in order to bring stem cell researchers and basic biologists together to 1) better understand the unique properties of embryonic stem cells and 2) to consider how embryonic stem cells might be exploited as a model system to advance the study of fundamental research problems. The report of that workshop can be found at http://www.nigms.nih.gov/news/reports/stemcellworkshop.html. The workshop report summarizes many fascinating opportunities to use HESC to study important biological problems and identifies activities that need to be addressed in order to stimulate and facilitate the use of HESC as a model system. These activities include: continued interdisciplinary collaborations and discussions between stem cell researchers and basic biologists; characterization of improved conditions for the growth of HESC and their maintenance in a pluripotent, undifferentiated state; characterization of molecular markers that distinguish HESC from more differentiated cells (including adult stem cells); and funding initiatives to encourage, enable and train basic biologists to work with HESC and to initiate pilot projects using HESC as a model system. As a result, NIGMS is issuing this RFA to stimulate HESC research and to address these immediate needs. Scope of Research The objective of this RFA is to encourage and enable basic biologists to work with HESC and to initiate pilot projects using HESC as a model system to study research problems that are central to the mission of NIGMS. NIGMS supports basic research that addresses fundamental biological questions. Applicants should visit the NIGMS website at http://www.nih.gov/nigms for detailed information on NIGMS areas of research interest. NIGMS does not support research that is targeted to specific organ systems or diseases. Areas of research that are appropriate for support by this RFA include: 1) studies on improved conditions for the growth of HESC and their maintenance in an undifferentiated state 2) further characterization of the unique molecular properties of HESC that distinguish them from other stem cell populations (e.g., adult stem cells) and from more differentiated cells 3) development of reagents that will facilitate the use of HESC as a model system 4) comparative studies of HESC and adult stem cells or animal stem cells 5) pilot studies on the use of HESC as a model system to address basic research problems that may include, but are not limited to: o regulation of gene expression and gene expression networks o epigenetic regulation of gene expression, including genomic imprinting o determinants of differentiation, dedifferentiation and nuclear reprogramming o chromosome, chromatin and telomere structure and function o regulation of cell proliferation o the basis of cell polarity and asymmetric cell division o signaling pathways required for cell adhesion and cell migration 6) pilot studies on the use of HESC as a primary cell type for drug discovery. NIGMS strongly encourages potential applicants to discuss their ideas with NIGMS program staff and to send a letter of intent prior to submission to ensure that the application will be responsive to the NIGMS mission and the intent of this RFA. Exploratory Center Grant Activities Exploratory Center Grants will be expected to: 1) establish and support institutional core facilities that can be used for the growth and maintenance of HESC, for the further characterization of HESC properties, and for development of reagents and tools that will enhance the use of HESC as a model system; 2) propose three pilot research projects that test the usefulness of HESC as a model system to address basic research problems; 3) provide research and training opportunities for graduate students and postdoctoral fellows interested in working with HESC; and 4) sponsor interdisciplinary workshops or meetings that foster an exchange of ideas and information between stem cell biologists and basic biologists. NIGMS expects to bring Exploratory Center Grant awardees to the NIH at least once during the term of the awards to discuss progress and exchange information. Travel funds should be budgeted for this purpose. MECHANISM OF SUPPORT This RFA will use the NIH P20 Exploratory Center Grant mechanism. Applicants will be solely responsible for planning, directing, and executing the proposed project. This RFA is a one-time solicitation with an expected award date in September, 2003. Although P20 Exploratory Grants will not be renewable, NIGMS expects to issue a subsequent RFA to support full-scale research centers, using the P50 mechanism. Such centers would have expanded core capabilities to grow and characterize HESC, to develop tools and reagents needed for HESC research, and to manage and disseminate experimental data. Such centers would be expected to support multiple research projects utilizing HESC to address important biological problems and to offer research training and community outreach activities. While award of a P20 Exploratory Grant may enhance an institution's subsequent ability to apply for a P50 Center Grant for HESC research, receipt of a P20 Exploratory Center award will not be a pre-requisite for submission of future P50 Center applications. This RFA uses just-in-time concepts and the non-modular budgeting format (see https://grants.nih.gov/grants/funding/modular/modular.htm). FUNDS AVAILABLE NIGMS intends to commit $2 million in FY 2003 to fund two to three new P20 Exploratory Grants in response to this RFA. An applicant may request a project period of three years and up to $500,000 direct costs per year. Costs for major items of equipment or indirect costs associated with consortium or sub-contractual arrangements will not be considered as part of the $500,000 direct cost limit. Because the nature and scope of the proposed research will vary from application to application, the size of each award also may vary. Although the financial plan of NIGMS sets aside funds to support this initiative, awards pursuant to this RFA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. Exploratory Center Grants will not be renewable. ELIGIBLE INSTITUTIONS You may submit an application(s) if your institution is a domestic organization and has any of the following characteristics: o 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 Applications from foreign institutions and for-profit organizations will not be accepted; however, subcontracts to foreign institutions and for-profit organizations may be included. 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 his/her institution to develop an application for support. Investigators are not required to have prior experience with HESC. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. SPECIAL REQUIREMENTS The Principal Investigator of the Exploratory Center Grant will be expected to commit a minimum effort of 25%. Applications may be considered for Federal funding only if the cell line(s) proposed for use is listed on the NIH Human Embryonic Stem Cell Registry (http://escr.nih.gov). Applications must specify the HESC cell line to be used and include the NIH identification number in the Description on page 2. Awards will not be made until access to eligible HESC is documented. 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: Marion Zatz, Ph.D. Division of Genetics and Developmental Biology NIGMS Building 45, Room 2AS-25E Bethesda, MD 20892-6200 Telephone: (301) 594-0943 Email: zatzm@nigms.nih.gov o Direct your questions about peer review issues to: Helen R. Sunshine, Ph.D. Office of Scientific Review NIGMS Building 45, Room 3AN.12F Bethesda, MD 20892-6200 Telephone: (301) 594-2881 Email: sunshinh@nigms.nih.gov o Direct your questions about financial or grants management matters to: Marcia Cohn Grants Management NIGMS Building 45, Room 2AN.44E Bethesda, MD 20892 Telephone: (301) 594-3918 Email: cohnm@nigms.nih.gov LETTER OF INTENT Prospective applicants are strongly urged 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 ascertain responsiveness to the RFA and IC mission as well as to estimate the potential review workload and plan the review. The letter of intent should be sent by the date listed at the beginning of this document to: Marion Zatz, Ph.D. Division of Genetics and Developmental Biology NIGMS Building 45, Room 2AS.25E Bethesda, MD 20892 Telephone: (301) 594-0943 Email: zatzm@nigms.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). The PHS 398 is available at https://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. The page limit for the narrative section (sections a-d) is 40 pages. This includes: (1) the overall description; (2) the research plan for the pilot projects and (3) the core(s). Please note that there is no requirement to submit this maximum number of pages; concise, articulate applications are desired. SUPPLEMENTAL INSTRUCTIONS: The identity of the stem cell lines to be used must be indicated in the Description on page 2 using official NIH identifier codes from the NIH Human embryonic stem cell registry http://escr.nih.gov. The P20 Exploratory Center Grant application should specify the administrative and organizational structure(s) that will be used to support the research, including: arrangements, where needed, to acquire expertise in growing and maintaining HESC; mechanisms to insure that participating investigators meet on a regular basis to exchange information; a description of plans for a scientific workshop; and opportunities to involve students and fellows in HESC research. 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: https://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 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: Helen R. Sunshine, Ph.D. Office of Scientific Review NIGMS 45 Center Drive, Room 3AN.12F Bethesda, MD 20892-6200 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. PEER REVIEW PROCESS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIGMS. Note that applicants are required to include the NIH code number identifying the eligible cell line that is to be used in the proposed research. Applications that do not provide this information will be returned without review. 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 NIGMS in accordance with the review criteria stated below. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a process in which all applications will be discussed and assigned a priority score o Receive a second level review by the National Advisory General Medical Sciences Council. 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 an application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning an application's overall score, weighting them as appropriate for each application. An 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 applicant may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. If the P20 Exploratory Center Grant application includes distinct subprojects, the scientific merit of each will be assessed, based on its merit as an independent effort and its potential importance/contribution to the success of the overall effort (however, the projects will not receive separate scores). (1) SIGNIFICANCE: Do the PI and other investigators address an important problem? If the aims of the pilot research projects 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 projects? Do the investigators acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Do the projects employ novel concepts, approaches or methods? Are the aims original and innovative? Do the projects challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATORS: Has the PI demonstrated the necessary experience, judgment and expertise to lead and manage the Center? Are the investigators appropriately trained and well suited to carry out this work? Is the work proposed appropriate to their experience level? (5) ENVIRONMENT: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed core and pilot projects take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: 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 (see Inclusion Criteria included in the section on Federal Citations, below). o BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. OTHER REVIEW CRITERIA: o Do the proposed plans for the core appear adequate to grow, maintain and further characterize HESC? o Are the choices of pilot projects good ones to exploit the unique potential of HESC as a model system? o If the investigators do not have prior experience or preliminary data using HESC, is their overall expertise consistent with proposed core activities and pilot studies using HESC? Have they adequately described plans to acquire additional expertise? RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: February 13, 2003 Application Receipt Date: March 13, 2003 Peer Review Date: June/July, 2003 Council Review: September, 2003 Earliest Anticipated Start Date: September, 2003 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 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: https://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 (https://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-001.html); a complete copy of the updated Guidelines are available at https://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 https://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 https://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 https://grants.nih.gov/grants/stem_cells.htm and at https://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 https://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. 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. 93.821; 93.862; 93.859 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 https://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 103-227, 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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