RESEARCH ON STEM CELL BIOLOGY AND CELL-BASED THERAPIES FOR HEART, LUNG, BLOOD, AND SLEEP DISORDERS RELEASE DATE: March 18, 2002 RFA: HL-02-019 National Heart, Lung and Blood Institute (NHLBI) (http://www.nhlbi.nih.gov) LETTER OF INTENT RECEIPT DATE: August 20, 2002 APPLICATION RECEIPT DATE: September 20, 2002 THIS RFA CONTAINS THE FOLLOWING INFORMATION o Purpose of this RFA o Research Objectives o Mechanism 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 Heart, Lung, and Blood Institute invites research grant applications to conduct research on stem cell biology and cell-based therapies for the treatment of cardiovascular, lung, blood, and sleep disorders and diseases. This initiative is intended to provide the scientific basis needed to accelerate translational research efforts leading to the use of cellular therapies for regenerative and reparative medicine. RESEARCH OBJECTIVES Background There are no effective therapies for many acquired and congenital cardiovascular, pulmonary, hematologic, and sleep disorders and diseases. Recent discoveries in stem cell biology present new opportunities for the use of cell-based therapies in disease areas with critical, unmet medical needs. Adult, cord blood, embryonic and fetal stem cells hold great potential for use in new strategies aimed at the regeneration and repair of damaged or diseased cardiovascular, lung, and blood tissues and may have potential value for improving treatment of sleep disorders. The plasticity of adult stem cells offers great promise as cell-based therapies. Hematopoietic stem cells give rise to all blood cells and have been used to treat serious blood disorders, malignant disease, and inherited diseases. It has been demonstrated that hematopoietic stem cells can differentiate into cardiac muscle cells, vascular cells, lung epithelium, neural cells, glial cells and other cell lineages. Recently the ability of transplanted or mobilized hematopoietic stem cells to engraft and repair heart muscle and vascular tissue damaged by ischemia has been demonstrated in animal models. In addition, bone marrow derived cells have been demonstrated to engraft as alveolar type 1 epithelial cells and as bronchial epithelial cells. Although hematopoietic and neuronal stem cell transplantation has not yet been applied to correcting central nervous system abnormalities associated with sleep disorders, such strategies potentially may have efficacy. Cardiovascular and lung tissues may also contain progenitor or stem cells that under the correct conditions could be induced to proliferate and repair cellular damage. For instance, recent findings suggest a sub-population of fetal proliferative alveolar epithelial stem cells is present in adult lung. In addition, other tissues such as skin, liver, brain, and muscle have progenitor or stem cell populations that may provide additional sources of cells for cellular therapies. The derivation of human embryonic stem (ES)cells has opened new avenues for using these cells for cellular therapies. The National Institutes of Health has recently outlined the implementation of federal funding for human ES cell research. ES cells are thought to be a truly pluripotent stem cell capable of self-renewal, can differentiate into all three germ cell layers, and have been shown to form hematopoietic cells and cardiomyocytes. Cells with these properties hold the promise of being able to repair or replace cells or tissues that are damaged or destroyed by many of the most devastating diseases and disabilities. One of the current advantages of using ES cells, as compared to adult stem cells, is that ES cells will proliferate in vitro, and have been used to generate a broad range of cell types through directed differentiation. It will be necessary to both identify the optimal stage(s) of differentiation for transplant, and demonstrate that the transplanted ES cell derived cells can survive, integrate, and function in the recipient. Currently, a major research goal is the control of the differentiation of human ES cell lines into specific kinds of cells, an objective that must be met if the cells are to be used as the basis for therapeutic transplantation, testing drugs, or screening potential toxins. Research Scope Clearly, the potential benefits of ES and adult stem cells to human health are immense. Combinations of blood cell lineages could be engineered to address specific patient needs and stem cells could be expanded to provide a crucial supply of universally matched, pathogen- free blood for transfusion. Since differentiated derivatives of stem cells could provide a unique supply of cells for transplantation, research to elucidate and understand the differentiation of these cells into specific cell types is critical. For tissue engineering applications, stem cells could be grown as biological substitutes for damaged and diseased cardiovascular, lung, or neural tissue, but understanding how to manipulate stem cells in order to grow biological substitutes is far from complete. If a patient"s own cells can be used to repair or regenerate damaged tissue, then understanding how to direct their stem cells or progenitors to the necessary cell lineages and tissue sites may be of key importance to the success of regenerative medicine. If the patient is to receive allogeneic stem cells, the questions of HLA-matching, immunosuppression, transplant rejection must be addressed. The number of stem cells available could limit clinical transplant applications and methods of obtaining, expanding and mobilizing stem cells need to be addressed. The durability of stem cell grafts also needs to be addressed to determine the length of time a cell-based therapy could benefit a patient. At a more fundamental level, stem cell differentiation could aid in the understanding of human cardiovascular, lung, blood, or neural development and lead to the identification of new cell differentiation factors. The regulation of hematopoietic stem cells may be mediated by different neurotransmitter mechanisms under conditions of sleep deprivation. Some serious cardiovascular and lung conditions, such as congenital heart defects and bronchopulmonary dysplasia, result from abnormal cell differentiation or arrested growth. A better understanding of the process of normal cell differentiation will allow further delineation of the fundamental errors that cause these diseases. It is anticipated that this initiative will focus on fundamental research on cell-based therapies directed at regenerative and reparative medicine for heart, lung, blood and sleep disorders and diseases. It is envisioned that areas of research supported under this initiative would include studies of the biology and characterization of embryonic, fetal and adult stem cells and progenitor cells important for heart, lung, blood and sleep disorders, studies of the use and differentiation of stem and progenitor cells for cell transplantation, and studies of stem cell homing to sites of tissue injury or specific tissue or organ sites, including the mechanisms underlying the homing process. Projects must focus on studies which could lead to cell-based therapies for heart, lung, blood, or sleep disorders or diseases. The potential relevance to specific diseases or disorders should be presented, and should be a consideration in the design of the research plan. Within this context, projects may include, but are not limited to, research in the following areas: o Stem and progenitor cell biology, evaluating and comparing a variety of cell sources and addressing their potential, frequency, availability, compatibility, trafficking or homing, and engraftment. This includes, but is not limited to, stem cells, progenitor cells, and embryonic stem cells. Studies could include gene expression profiling for a variety of cell types. o Determination of the best source of stem cells for cell-based therapies such as comparison of somatic (adult) stem cells and ES cells. o Issues affecting the utility of various stem cells for cellular therapy, such as the rarity of adult stem cells, presence of infectious agents in stem cell populations, and the tumorigenic potential of ES cells. o Stem cell identification, isolation, purification, in vitro (ex vivo) expansion, and immortalization. o Manipulation of stem cell self-renewal and commitment. o Role of growth factors, cytokines, receptors, transmembrane signaling, marrow stroma and microenvironment, and adhesive proteins in stem cell interactions and hematopoiesis. o Stem cell transplantation, stem cell mobilization, and in situ activation of resident tissue stem cells. o Enhancing stem cell engraftment through manipulation of stem and progenitor cell homing receptors in the target organ and on the stem cell surface. o Development of animal models for cell-based therapy using stem cells. o Histocompatibility and allo-interactions, mechanism of induction of transplant tolerance, minimizing the graft vs. host effect and graft rejection. Projects may not include research in the following areas: o Applications including research on somatic cell nuclear transfer, also known as nuclear transfer, will not be eligible for consideration and will be returned to the applicant. MECHANISM OF SUPPORT This RFA will use NIH individual research project grants (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 July 1, 2003. This RFA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non-modular research grant applications. FUNDS AVAILABLE The National Heart, Lung, and Blood Institute (NHLBI) intends to commit approximately $8 million in FY 2003 to fund 12 to 15 new and/or competitive continuation 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 $350,000 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 NHLBI 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 governments o Eligible agencies of the Federal government o Domestic or foreign 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 In order to be responsive to this RFA, applications must focus on studies which could lead to cell-based therapies for heart, lung, blood, or sleep disorders or diseases. The potential relevance to specific diseases or disorders must be presented, and should be a consideration in the design of the research plan. In addition, applications including research on somatic cell nuclear transfer, also known as nuclear transfer, will not be eligible for consideration and will be returned to the applicant. Upon initiation of the program, the NHLBI will sponsor annual meetings to encourage the exchange of information among investigators who participate in this program, perhaps in conjunction with other Institute sponsored cell-based therapy or 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 INQUIRIES We encourage inquiries concerning this RFA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research or financial/grants management issues: o Direct your questions about scientific/research issues to: Dr. John W. Thomas Division of Blood Diseases and Resources / NHLBI 6701 Rockledge Drive /Room 10154 / Mail Stop 7952 Bethesda, MD 20892-7950 Telephone: (301) 435-0050 FAX: (301) 451-5453 Email: ThomasJ@nhlbi.nih.gov Dr. Mary Ann Berberich Division of Lung Diseases / NHLBI 6701 Rockledge Drive /Room 10102 / Mail Stop 7952 Bethesda, MD 20892-7952 Telephone: (301) 435-0222 FAX: (301) 480–3557 E-mail: BerberiM@nhlbi.nih.gov Dr. John Fakunding Division of Heart and Vascular Diseases / NHLBI 6701 Rockledge Drive /Room 9170 / Mail Stop 7940 Bethesda, MD 20892-7940 Telephone: (301) 435-0494 FAX: (301) 480–1336 E-mail: FakundiJ@nhlbi.nih.gov o Direct your questions about financial/grants management matters to: Marsha Mathis National Heart, Lung, and Blood Institute 6701 Rockledge Drive / Room 7158 / Mail Stop 7926 Bethesda, MD 20817-7926 Telephone: (301) 435-0170 FAX: (301) 480-3310 Email: MathisM@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 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 NHLBI 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 Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7178 (MSC 7924) Bethesda, MD 20892-7924 (20817 for Courier) Telephone: (301) 435-0270 Fax: (301) 480-0730 Email: ClarkA@nhlbi.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 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 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 as well as all five sets of the appendix material must be sent to: Anne P. Clark, Ph.D. Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7178 (MSC 7924) Bethesda, MD 20892-7924 (20817 for Courier) Telephone: (301) 435-0270 Fax: (301) 480-0730 Email: 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 (IC). 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 (IC) 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 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 second level review by the Heart, Lung and Blood National Advisory 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 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 Innovation o Investigator o 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 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. RECEIPT AND REVIEW SCHEDULE Letter of Intent Receipt Date: August 20, 2002. Application Receipt Date: September 20, 2002. Peer Review Date: February/March 2003. Council Review: May 29-30, 2003. Earliest Anticipated Start Date: July 1, 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: 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_2 001.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 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 103-227, 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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