PA-01-078: THE BIOLOGY OF NON-HUMAN STEM CELLS IN THE ENVIRONMENT OF THE NERVOUS SYSTEM

Department of Health
and Human Services (HHS)

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This Program Announcement expires on April 30, 2004, unless reissued. THE BIOLOGY OF NON-HUMAN STEM CELLS IN THE ENVIRONMENT OF THE NERVOUS SYSTEM Release Date: April 9, 2001 PA NUMBER: PA-01-078 National Institute of Neurological Disorders and Stroke (http://www.ninds.nih.gov) National Institute of Mental Health (http://www.nimh.nih.gov) National Institute on Deafness and Other Communication Disorders (http://www.nidcd.nih.gov/) National Institute on Aging (http://www.nih.gov/nia/) National Institute of Child Health and Human Development (http://www.nichd.nih.gov/) THIS PA USES "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. THIS PA INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING AN APPLICATION IN RESPONSE TO THIS PA. PURPOSE The National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Mental Health (NIMH), the National Institute on Deafness and Other Communication Disorders (NIDCD), the National Institute on Aging (NIA) and the National Institute of Child Health and Human Development (NICHD) are committed to the discovery of effective treatments for neurological disorders, and invite applications for studies on the biology of non-human stem cells and regulation of their replication, development and function in the nervous system. The tremendous plasticity exhibited by stem and progenitor cells raises the possibility that they can be used to replace components and restore function to parts of the brain that have been compromised by congenital disorders, developmental malfunction, injury or disease. There is, however, little understanding of the behavior and regulation of these cells in the environment of the healthy brain, or in the nervous system altered by such conditions as stroke, trauma, spinal cord injury, sensory loss, Muscular Dystrophy, Amyotrophic Lateral Sclerosis, Parkinson’s Disease, Huntington’s Disease, Alzheimer’s Disease, Multiple Sclerosis or mental illness. There are few studies on the long-term fates of transplanted cells within the nervous system or at other sites within the host. An understanding of environmental cues, age-dependent processes and genetic factors that govern the activities of these cells is crucial in order to develop safe and effective cell-replacement treatments. This Program Announcement encourages applications for support of ground-breaking research on non-human stem cells that address these issues. RESEARCH OBJECTIVES Background One of the most exciting frontiers in medicine is the potential use of stem cells for treating congenital or degenerative disorders. In the central nervous system (CNS), cell-replacement strategies are of particular interest because, unlike other tissues, the mature brain and spinal cord have little capacity for self-repair. CNS neurons are very restricted in their ability to regrow in situ, and the adult brain appears to have a limited ability to produce new neurons. Recent reports of multipotent cells that are able to generate cells with neuronal properties have raised expectations that such cells might be used to replace lost neurons and glia, repair defective circuits, and restore functions compromised by age, physical damage or disease. The hope is that, when exposed to the optimal microenvironment, stem cells will differentiate in a manner appropriate to the local brain region, and integrate seamlessly with the existing circuits of the host. For this to occur, the stem or progenitor cell should respond to proliferative and/or guidance cues that are either induced by the injury or degeneration, or supplied exogenously, but subsequently turn off these programs once normal cell numbers and circuitry have been attained. Whether stem cells can fulfill all these criteria in all areas of the nervous system remains to be determined, however, recent results obtained from studies in non-human model systems are encouraging. Transplanted neuroblasts appear responsive to local cues. They can migrate to and repopulate degenerating parts of the adult brain, express the correct transmitters and make synaptic contacts with host neurons. In the diseased retina, precursor cells differentiate into new neurons that appear to incorporate into local circuitry. In rodent models of Parkinson’s Disease, precursor cells induce functional recovery, if differentiated into dopaminergic neurons before transplantation into the striatum. Oligodendrocytes derived from murine embryonic stem cells replaced lost myelin in the injured adult spinal cord. Together, these results demonstrate the ability of stem cells to differentiate and integrate appropriately into the damaged or diseased CNS. Another promising area of research lies in exploring the extent to which precursor cells derived from non-neural tissues, or from different stages of development, can generate specific classes of neurons and glia that can be used to repair particular neural circuits. While it is not surprising that murine embryonic stem cells can differentiate spontaneously into heart, blood, bone, and neuronal cells, unspecialized cells derived from adult sources as diverse as muscle, brain and bone marrow have recently been shown to trans-differentiate and acquire properties of cells from other lineages. Most intriguing, cells that appear committed to a particular lineage may de- differentiate to a more pluripotent state. These aspects of plasticity raise the hope for autologous transplants. The concern, however, also arises that transplanted cells could be triggered by the local environment to change once again into an undesired phenotype with unpredictable consequences. Examples of the enormous plasticity exhibited by stem cells raise fundamental questions regarding the comparative potential of precursor cells derived from different species, tissue sources and stages of development, the nature of the local environment that regulates stem cell behavior, and the genetic, molecular and cellular mechanisms that result in functional integration within the host. Understanding the normal process of stem cell differentiation during development provides a crucial baseline to assess their behavior in the environment provided by an adult host. This type of information could be obtained from studies conducted in vitro as well as in appropriate animal models. Recent findings demonstrate that in select regions of the avian and mammalian nervous systems, endogenous neural stem and precursor cells continue to produce new neurons and circuits throughout adulthood, and indeed over the entire lifespan. Hair cells of the inner ear can be replaced following acoustic and drug-induced damage in the adult avian and amphibian nervous systems. Interestingly, behavior and experience can have profound effects on neurogenesis in the adult and the aging brain. These preliminary findings have important implications for development, learning, memory and the maintenance of a healthy and functional nervous system into old age. The processes that regulate the native production of new neurons may be deployed to repair disordered regions of the brain. In addition, elucidation of these processes may provide insight into the functional basis of neurodevelopmental disorders, as well as errors in the establishment of neural circuitry leading to malfunction during puberty, adulthood and in old age. New research into mechanisms that influence neurogenesis and gliogenesis will provide fundamental information on the capacity of the nervous system to adapt in response to pharmacological and behavioral therapy throughout life. Objectives and Scope This Program Announcement is intended to promote the exploration of non-human stem cell biology in the nervous system. Research efforts on cellular, molecular and genetic mechanisms that influence the lineage choices of stem cells are of particular interest, as are studies that explore the long-term fates of stem cell-derived populations in animal models. 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 neural and non-neural progenitor cells in vitro and in vivo. o Comparison of the structural and functional integration of different types of progenitor cells into host nervous system, and in hosts of different ages. o Comparison of the functional properties of neural precursor cells implanted at different stages of differentiation. o Characterization of the migratory properties of stem cells in the developing, adult or aging nervous system. o Investigation of the ability of progenitor cells to revert to a more plastic, multipotent state. o Examination of changes in gene and protein expression as stem and progenitor cells differentiate along specific lineages. o Identification of signals, signaling pathway components and transcriptional factors that regulate the fate(s) of transplanted cells in the nervous system. o Development of in vivo and in vitro assays that permit accurate and reliable characterization of the state of differentiation of stem or precursor cells. o Development of informatics models that integrate the results from studies of different stem and precursor cell types, and provide reliable predictions about changes in the state of the cells as a result of environmental cues. o Identification, characterization and validation of animal model systems, including models of disease and aging for screening and comparing the functional capabilities of implanted stem cells. o Comparison of the efficacy and risks of different modes of cell delivery in large and small mammals, and in animals of different ages. o Assessment of the ability of transplanted cells to integrate with the host nervous system and modify dysfunctional states. o Development of novel techniques such as non-invasive methods to track the integration and/or function of transplanted cells. o Assessment of the long-term fates of and the consequences of transplanted cells and their progeny in ectopic sites within the host. o Assessment of the effects of environmental changes, therapies, or rehabilitation strategies on the production, differentiation and survival of endogenous stem cells across the lifespan. 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. Support for the R21 grants is limited to two years with a maximum of $100,000 direct costs requested 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. 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 Beth-Anne Sieber, Ph.D. Chief, Developmental Neurobiology Program Division of Neuroscience and Basic Behavioral Science National Institute of Mental Health Neuroscience Center, Room 7186 Bethesda, MD 20892 Telephone: (301) 443-5288 FAX: (301) 402-4740 Email: sieberb@helix.nih.gov Nancy L. Freeman, Ph.D. Scientific Program Director National Institute on Deafness and Other Communication Disorders National Institutes of Health Executive Plaza South-400C 6120 Executive Blvd. MSC-7180 Rockville, MD 20892-7180 Telephone: (301) 402-3458 FAX: (301) 402-6251 Email: Nancy_Freeman@NIH.gov Bradley C Wise, Ph.D. Program Director, Fundamental Neuroscience Neuroscience and Neuropsychology of Aging Program National Institute of Aging Gateway Building, Suite 3C307 7201 Wisconsin Avenue MSC 9205 Bethesda, MD 20892-9205 Telephone: (301) 496-9350 FAX: (301) 496-1494 Email: WiseB@nia.nih.gov Ralph M. Nitkin, Ph.D. Biological Sciences and Career Development Program National Center for Medical Rehabilitation Research National Institute of Child Health and Human Development Executive Building, Room 2A03 6100 Executive Blvd, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 402-4206 FAX: (301) 402-0832 Email: rn21e@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) 496-7488 FAX: 301-402-0219 Email: rr46w@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 Sherry Dabney Grants Management Officer Division of Extramural Activities National Institute on Deafness and other Communication Disorders 6120 Executive Boulevard MSC-7180 Rockville, Maryland 20892 (overnight mail) Rockville, Maryland 20850 Telephone: (301)402-0909 FAX 301/402-1758 Email:sd63u@nih.gov Linda Whipp Grants Management Officer Grants and Contracts Management Office Gateway Building, Suite 2N212 Bethesda, Maryland 20892-9205 Telephone: (301) 496-1472 FAX: (301) 402-3672 Email:WhippL@nia.nih.gov Christopher Myers Grants Management Branch National Institute of Child Health and Human Development Building 61E, Room 8A01, MSC 7510 6100 Executive Boulevard Bethesda, MD 20892-7510 Telephone: 301-435-6996 Email: cm143g@nih.gov APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 4/98) and will be accepted at the standard application deadlines as indicated in the application kit. Application kits are available at most institutional offices of sponsored research and may be obtained from the Division of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: GrantsInfo@nih.gov. For R21 applications, use form PHS 398, with the following modifications: 1. Face Page of the application: Item 2, Check the box marked "Yes" and type the title (R21 Program). The title and number of the program announcement must also be typed on line 2 of the face page of the application form. 2. Description: As part of the description, explain briefly how this application relates to the purpose of the R21 mechanism as stated in this program (i.e. generating pilot data in a potentially important area or developing innovative methodologies or concepts that will produce significant breakthroughs in an area of established importance. 3. Research Plan: Color/glossy photos may be submitted as an appendix, however, the appendix may not be used to circumvent the page limitation. Letters of recommendation are not considered appendices, and do not count towards the 15-page limit. Applicants planning to submit an investigator-initiated R01 application 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. This policy requires an applicant to obtain agreement for acceptance of both any such application and any such subsequent amendment. Refer to the NIH Guide for Grants and Contracts, March 20, 1998 at http://grants.nih.gov/grants/guide/notice-files/not98-030.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 Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. BUDGET INSTRUCTIONS Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.) The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, list all project personnel, including their names, percent of effort, and roles on the project. No individual salary information should be provided. However, the applicant should use the NIH appropriation language salary cap and the NIH policy for graduate student compensation in developing the budget request. For Consortium/Contractual costs, provide an estimate of total costs (direct plus facilities and administrative) for each year, each rounded to the nearest $1,000. List the individuals/organizations with whom consortium or contractual arrangements have been made, the percent effort of all personnel, and the role on the project. Indicate whether the collaborating institution is foreign or domestic. The total cost for a consortium/contractual arrangement is included in the overall requested modular direct cost amount. Include the Letter of Intent to establish a consortium. Provide an additional narrative budget justification for any variation in the number of modules requested. o BIOGRAPHICAL SKETCH - The Biographical Sketch provides information used by reviewers in the assessment of each individual"s qualifications for a specific role in the proposed project, as well as to evaluate the overall qualifications of the research team. A biographical sketch is required for all key personnel, following the instructions below. No more than three pages may be used for each person. A sample biographical sketch may be viewed at: http://grants.nih.gov/grants/funding/modular/modular.htm - Complete the educational block at the top of the form page, - List position(s) and any honors, - Provide information, including overall goals and responsibilities, on research projects ongoing or completed during the last three years. - List selected peer-reviewed publications, with full citations, o CHECKLIST - This page should be completed and submitted with the application. If the F&A rate agreement has been established, indicate the type of agreement and the date. All appropriate exclusions must be applied in the calculation of the F&A costs for the initial budget period and all future budget years. o The applicant should provide the name and phone number of the individual to contact concerning fiscal and administrative issues if additional information is necessary following the initial review. 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, 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 grants: 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? AWARD CRITERIA Applications will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: Quality of the proposed project as determined by peer review, availability of funds, and program priority. 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. 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), The biology of stem cells in the environment of the nervous system, 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. 93.853, 93.242, 93.173, 93.866 and 93.929. Awards are made under authorization of sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant 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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