This Program Announcement expires on November 30, 2004, unless reissued. PLASTICITY OF HUMAN STEM CELLS IN THE NERVOUS SYSTEM Release Date: December 3, 2001 PA NUMBER: PA-02-025 National Institute of Neurological Disorders and Stroke (http://www.ninds.nih.gov) National Institute on Aging (http://www.nia.nih.gov) National Institute of Mental Health (http://www.nimh.nih.gov) National Heart, Lung, and Blood Institute (http://www.nhlbi.nih.gov) THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. MODULAR INSTRUCTIONS MUST BE USED FOR RESEARCH GRANT APPLICATIONS UP TO $250,000 PER YEAR. MODULAR BUDGET INSTRUCTIONS ARE PROVIDED IN SECTION C OF THE PHS 398 (REVISION 5/2001) AVAILABLE AT http://grants.nih.gov/grants/funding/phs398/phs398.html. PURPOSE The National Institute of Neurological Disorders and Stroke (NINDS), the National Institute on Aging (NIA), the National Institute of Mental Health (NIMH) and the National Heart, Lung, and Blood Institute (NHLBI) invite applications for studies on the plasticity and behavior of human stem cells, and regulation of their replication, differentiation and function in the nervous system. Because of their ability to generate neurons and glia, stem cells are promising candidates for the development of cellular and genetic therapies for neurological disorders, including congenital, neurodevelopmental, neuropsychiatric and neurodegenerative diseases, as well as neuroregulatory problems in heart, lung, and blood diseases, and sleep disorders. Animal studies demonstrate that stem or progenitor cells can be derived from a variety of tissues and from hosts of different ages; however, the requirements and potential for differentiation of each cell type appears to be unique. In a recently-issued Program Announcement (PA-01-078)), NINDS and other institutes at NIH invited studies to investigate the influence of extrinsic signals in the nervous system on the biology of non-human stem cells. Development of treatments for human conditions ultimately will require understanding the biology of human stem cells. To achieve this goal, NINDS, NIA, NIMH and NHLBI encourage applications to study the fundamental properties of all classes of human stem cells, and to confirm, extend, and compare the behavior of human stem cells that are derived from different sources and ages or exposed to different regimes in vitro and in vivo. Of high priority are studies to develop methods for identifying, isolating and characterizing specific human precursor populations at intermediate stages of differentiation into neurons and glia. Because our current understanding of stem cell biology comes mainly from studies conducted on murine stem cells, a comparison between human and non-human cells will be crucial for translating the results of animal studies to clinical trials. This Program Announcement (PA) invites applications for support of research that characterizes cellular, molecular and genetic mechanisms that allow human stem and precursor cells to express plasticity and lineage choices. Projects that address comparisons between different classes of human stem cells, and between human and non-human stem cells would also be directly relevant to this PA. RESEARCH OBJECTIVES Background Stem cell research offers enormous potential for treating a host of congenital, developmental, psychiatric or degenerative diseases for which there are no cures. In animal studies, multipotent progenitor cells from many different sources have been reported to generate cells with neuronal or glial properties, raising expectations that they could be used to replace lost neurons and glia, repair defective circuits, and restore functions compromised by abnormal development, age, physical damage or disease. In addition to cell and tissue therapy, the ability to selectively produce one or more differentiated cell types at will from pluripotent stem cells would be of clinical importance in investigating the effects of drugs and environmental factors on differentiation and cell function in the human nervous system. Major challenges have to be overcome before any human cells can be harnessed and translated to meaningful treatments for patients. These challenges include identifying the optimal type of stem cell or stem cell derivative for specific assays and therapies for individual disorders, harvesting and growing sufficient quantities of the appropriate cell type, deciding the best therapeutic strategy for each condition to be treated, and assessing the often-unexpected side effects that may arise when such versatile cells are introduced into a patient. In addition, examples of the enormous plasticity exhibited by stem cells raise fundamental questions about the comparative potential of precursor cells derived from different sources and different stages of development; the nature of the conditions that regulates stem cell behavior; and the genetic, molecular and cellular mechanisms that result in functional integration within the host nervous system over the lifespan of the organism. Of the many types of progenitor cells competent to develop neuronal and glial features, embryonic stem (ES) cells, derived from embryos at the blastocyst stage, may have the broadest natural potential because, during development, they normally produce all the cells of an organism. These pluripotent cell lines are characterized by nearly unlimited self-renewal and differentiation capacity. During differentiation in vitro, mouse and human ES cells express properties of mature tissues such as muscles, several classes of neurons, glia, pancreatic islet cells, cartilage and blood. When transplanted into the central nervous system (CNS), ES cells that have been coaxed along an oligodendrocytic lineage will form myelin and ensheath axons. Some improved function was reported in rodent models of demyelination and spinal cord injury that received these ES cell-derived transplants. However, how the transplanted cells contributed to the restoration of function is unclear. Another source of progenitors are neural stem cells that are derived from neurogenic regions in the developing and adult CNS. They integrate seamlessly into the host when transplanted into the developing nervous system, but their fate appears highly dependent upon the local environment that they encounter. This is particularly true when these cells are introduced into the adult CNS. Cells that can become neurons in the hippocampus, generate only astrocytes when placed into the spinal cord. Under appropriate conditions, some neural stem cells can even develop into non-neural cell types. Of particular interest are recent reports from a number of investigators that stem cells present in adult, non-neuronal tissues also appear to show surprising plasticity or versatility. For example, under specific culture conditions, bone marrow stromal cells can give rise to cells with neuronal or glial features. Following bone marrow transplantation, donor-derived cells could be found in many tissues including the CNS, skeletal muscle, liver, heart, vascular endothelia, and bone. One group reports that systemic injections of bone marrow stromal cells resulted in significant functional recovery in a rodent model of ischemia. Before we can design therapies using human stem cells, we must understand how "plastic" or malleable are these different classes of cells, the environmental cues that drive their choice of fates, and how reversible are these fates. For unknown reasons, select populations of cells are destroyed in specific neurological disorders and diseases - dopaminergic neurons in Parkinson's Disease (PD), cholinergic neurons in Alzheimer's Disease(AD), motor neurons in Amyotrophic Lateral Sclerosis (ALS) and myelinating oligodendrocytes in Multiple Sclerosis (MS). Because there is great diversity of neurons and glia, studies to develop treatments for these and other diseases with less well defined etiologies will require the characterization and acquisition of unique populations of neurons and glia. While dopaminergic neurons clearly are the target of studies on PD, defining the specific features of the dopaminergic neurons needed to treat PD is less obvious. Each neuronal and glial phenotype is defined by a constellation of morphological, biochemical, genetic, and electro-physiological properties, and the functional significance/impact of a neuronal population depends on connectivity with appropriate afferent and efferent populations. It is necessary to determine the particular stem cell and protocol to generate a differentiated phenotype that best replicates the significant properties of the endogenous target cell. This requires direct comparison in the same in vitro and in vivo assay systems between the numerous types of stem and progenitor cells. The easiest features to evaluate include morphology, biochemical and gene expression, and physiology. Less often described are quantification of protein and gene levels, acquisition and maintenance of phenotype over time, cell division and migration, and the simultaneous tracking of multiple properties in a population of cells. Least studied is the functional integration and functional consequences of the transplanted cells in the host, and the long- term behavior of the transplanted population within the host. At present we know little about the biology and comparative differentiation potential of different types of stem cells, or their potential for use in developing treatments for neurological disease. Much of our understanding of the neural potential of different stem cells comes from animal studies. It is still unclear if the many varieties of stem cells described in animals are also present in humans, or how they can be harvested, expanded, purified and induced to differentiate into neurons and glia. We lack an understanding of the conditions required to support the development of human cells along specific lineages in a reproducible manner. Because most studies on human stem cells have been conducted in culture, it is unclear whether the differentiated cells will persist, how they will behave in the environment of the healthy brain, or their potential in the nervous system altered by trauma, disease, or age. A few studies, carried out in animal models of dysfunction, hold promise that differentiated donor cells can maintain neuronal markers for long periods in vivo. However, there is as yet no demonstration that these cells integrate functionally into the existing nervous system of the host and contribute to behavioral recovery. There are few studies on the long-term fates of any transplanted cells within the nervous system or at other sites within the host. Objectives and Scope This Program Announcement is intended to promote studies of human stem cell biology and the regulation and control of stem cells in the nervous system. Of special interest are research efforts on cellular, molecular and genetic mechanisms that influence the lineage choices of human stem cells, and the development of methods for isolating specific cell populations, and studies that demonstrate or enhance the safety of human stem cells in treatments for neurological conditions. The following examples illustrate areas that are of high interest; other innovative projects are also encouraged. o Comparison of the mitotic potential and fates of different types of human stem and progenitor cells in vitro and in vivo in the CNS. o Comparison of the structural and functional integration of different types of human progenitor cells into the healthy versus the injured or diseased host nervous system. o Determination of the functional properties of human progenitor cells implanted during progressive developmental stages of the host CNS, and with aging. o Comparison of the functional properties of human stem and precursor cells implanted at different stages of differentiation along neuronal or glial lineages. o Comparison of the behavior of human stem cells with that of their non- human counterparts in vitro and in vivo. o Investigation of the ability of different human stem cells to revert to a more plastic, multipotent state, under normal conditions and following injury. o Examination of changes in gene and protein expression as human stem and progenitor cells differentiate along specific neuronal and glial lineages. o Identification of signals, signaling pathway components and transcriptional factors that regulate the fate(s) of transplanted human stem cells and their derivatives. o Development of assays and markers that permit accurate and reliable characterization of the state of differentiation of human stem or neural precursor cells. o Development of methods for identifying, isolating and enriching select human precursor populations, intermediate states, and differentiated neuronal and glial phenotypes. o Development of a public database of gene expression patterns for human stem cells as they differentiate and mature into specific neuronal and glial fates. o Development of informatics models that integrate the results from studies of different human and non-human stem and neural precursor cell types. o Use of animal model systems of neurological and neuropsychiatric disorders for screening and comparing the functional capabilities of implanted human stem cells and their progeny. o Assessment of the long-term fates and the consequences of transplanted human cells and their progeny in the nervous system, and in ectopic sites within the host. o Assessment of the connectivity and integration of transplanted cells within the host nervous system and across the lifespan. o Assessment and comparison of the immune responses generated by different human stem cells and their progeny in the host. o Assessment of the behavior of host cells in response to the short-term and long-term presence of transplanted human stem cells and/or their derivatives. SPECIAL REQUIREMENTS Use of human embryonic stem cells (hESCs): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. All cell lines that meet these criteria and are therefore eligible for research with federal funding are identified and registered in the NIH Human Embryonic Stem Cell Registry (http://escr.nih.gov). NIH has established a website (http://grants.nih.gov/grants/stem_cell_faqs.htm) that provides information in the form of answers to frequently asked questions about implementation issues for human embryonic stem cell research (see also: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-014.html). Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for funding. Each approved cell line is specifically identified by an NIH code in the Registry. It is the responsibility of the applicant to provide in their application the official NIH identifier(s)for the hESC line(s)that they will use as found in the NIH Registry (http://escr.nih.gov). Applications that do not provide this information will be returned without review. MECHANISM OF SUPPORT The Exploratory/Developmental Grants (R21) mechanism and the Research Project (R01) grant mechanism will be used to support projects under this Program Announcement(PA). Under these mechanisms, responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The proposed project period during which the research will be conducted should adequately reflect the time required to accomplish the stated goals and should be no more than 5 years for R01 grants. The R21 grants are one-time awards to support innovative, high impact research projects that would either 1) generate pilot data to assess the feasibility of a novel avenue of investigation, 2)involve high risk experiments that could lead to a breakthrough in a particular field, or 3) demonstrate the feasibility of new technologies that could have major impact in a specific area. For this PA, participating NIH institutes will use the NINDS guidelines for the R21 mechanism, which can be found at http://www.ninds.nih.gov/funding/r21guidelines.htm. As described in these guidelines, R21 proposals are limited to two years with a maximum of $125,000 direct costs per year. This program is appropriate both for new investigators seeking to establish independent research careers and for established investigators wishing to explore new areas of neuroscience or develop novel technologies. Specific application instructions have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts that have been adopted by the NIH. Complete and detailed instructions and information on Modular Grant applications have been incorporated into the PHS 398 (rev. 5/2001). Additional information on Modular Grants can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. 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. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding programmatic issues to: Arlene Y. Chiu, Ph.D. Program Director, Repair and Plasticity Program National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 2206, MSC 9525 Bethesda, MD 20892-9525 Telephone: (301) 496-1447 FAX: (301) 480-1080 Email: chiua@ninds.nih.gov Bradley C. Wise, Ph.D. Program Director, Fundamental Neuroscience Neuroscience and Neuropsychology of Aging Program National Institute on Aging 7201 Wisconsin Avenue, Suite 3C307 MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: wiseb@nia.nih.gov Beth-Anne Sieber, Ph.D. Chief, Developmental Neurobiology Program National Institute of Mental Health Neuroscience Center, Room 7186, MSC 9641 Bethesda, MD 20892-9641 Telephone: (301) 443-5288 FAX: (301) 402-4740 Email: sieberb@helix.nih.gov John W. Thomas, Ph.D. Blood Diseases Program Division of Blood Diseases and Resources National Heart, Lung, Blood Institute Two Rockledge Centre, Room 10154, MSC 7950 6701 Rockledge Drive Bethesda, MD 20892-7950 Telephone: (301) 435-0050 FAX: (301) 451-5453 Email: ThomasJ@nhlbi.nih.gov Direct inquiries regarding fiscal matters to: Rita Sisco Grants Management Specialist Grants Management Branch , DER National Institute of Neurological Disorders and Stroke Neuroscience Center, Room 3290, MSC 9537 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: rr46w@nih.gov Linda Whipp Grants Management Officer Grants and Contracts Management Office National Institute on Aging 7201 Wisconsin Avenue, Suite 2N212, MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email: lw17m@nih.gov Diana S. Trunnell Grants Management Branch National Institute of Mental Health 6001 Executive Boulevard, Room 6115, MSC 9605 Bethesda, MD 20892-9605 Telephone: (301) 443-2805 FAX: (301) 443-6885 Email: Diana_Trunnell@nih.gov Suzanne A. White Division of Extramural Affairs National Heart, Lung, and Blood Institute 6701 Rockledge Drive, Room 7154 (MSC 7926) Bethesda, MD 20892-7926 Telephone: (301) 435-0166 FAX: (301) 480-3310 Email: WhiteSa@NHLBI.NIH.GOV APPLICATION PROCEDURES The PHS 398 research grant application instructions and forms (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html must be used in applying for these grants and will be accepted at the standard application deadlines (http://grants.nih.gov/grants/dates.htm) as indicated in the application kit. This version of the PHS 398 is available in an interactive, searchable format. Beginning January 10, 2002, however, the NIH will return applications that are not submitted on the 5/2001 version. For further assistance contact GrantsInfo, Telephone 301/435-0714, Email: GrantsInfo@nih.gov. Applicants planning to submit an investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended/revised version of the preceding grant application types requesting $500,000 or more in direct costs for any year are advised that he or she must contact the Institute or Center (IC) program staff before submitting the application, i.e, as plans for the study are being developed. Furthermore, the application must obtain agreement from the IC staff that the IC will accept the application for consideration for award. Finally, the applicant must identify, in a cover letter sent with the application, the staff member and Institute or Center who agreed to accept assignment of the application. The current policy on accepting applications requesting $500K or more requires PIs to seek agreement from IC staff at least 6 weeks prior to submission date. Refer to the NIH Guide for Grants and Contracts, October 16, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. The title and number of the program announcement must be typed on line 2 of the face page of the application form and the YES box must be marked. Submit a signed, typewritten original of the application, including the Checklist, and five 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) SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS 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 NIH staff. The research grant application form PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html is to be used in applying for these grants, with modular budget instructions provided in Section C of the application instructions. REVIEW CONSIDERATIONS Applications will be assigned on the basis of established PHS referral guidelines. Applications will be evaluated for scientific and technical merit by an appropriate scientific review group convened in accordance with the standard NIH peer review procedures. 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 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, for R01 applications, 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. (6) For R21 applications: Could these high risk experiments lead to a breakthrough in the field? Could the proposed studies demonstrate the feasibility of new technologies that could have a major impact in a specific area? 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 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. 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 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 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: http://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. REQUIRED EDUCATION IN THE PROTECTION OF HUMAN RESEARCH PARTICIPANTS NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. This policy announcement is available in the NIH Guide for Grants an Contracts, June 5, 2000 (Revised August 25, 2000), available at: http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. 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. 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 Program Announcement (PA), " Plasticity of human stem cells in the nervous system," is related to several of the priority areas including working toward improving life expectancy and quality of life of patients disabled by neurological disorders. 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. 93.853, 93.866, 93.242 and 93.839. 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 NIH Grants Policy Statement is available at http://grants.nih.gov/grants/policy/policy.htm. This document includes general information about the grant application and review process; information on the terms and conditions that apply to NIH grants and cooperative agreements; and a listing of pertinent offices and officials at the NIH. The PHS strongly encourages all grant and contract 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, and 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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