PILOT STUDIES FOR RE-ESTABLISHING CONNECTIVITY IN SPINAL CORD INJURY Release Date: March 9, 2000 RFA: NS-01-001 National Institute of Neurological Disorders and Stroke Letter of Intent: August 15, 2000 Application Receipt Date: October 11, 2000 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS IN RESPONSE TO THIS RFA. PURPOSE Motor vehicular accidents, sports accidents, and assaults result in about 10,000 new cases of spinal cord injury (SCI) every year in the United States. Damaged nerve fibers within the cord cease to relay signals between the brain and the rest of the body, depending on the site of damage along the spinal cord, these injuries can interfere with breathing, bowel and bladder function, and result in paraplegia or quadriplegia. New findings on the molecular regulation of axonal pathfinding and synapse formation during development suggest that similar mechanisms could lead to more robust and directed nerve regrowth in adulthood, and the restoration of connections within the damaged spinal cord. However, more information is needed on the expression of such signals in the normal and injured adult spinal cord. In order to stimulate research in this area, the National Institute of Neurological Disorders and Stroke (NINDS) invites applications for support of pilot studies that extend the new discoveries in developmental neurobiology to stimulate axonal regeneration, guidance, and synaptogenesis within the injured spinal cord. Researchers with expertise in development and other disciplines are encouraged to initiate exploratory studies leading to a better understanding of the basic mechanisms that contribute to repair and plasticity after spinal cord injury. RESEARCH OBJECTIVES Background In the adult mammalian central nervous system (CNS), damage to white matter tracts results in the complete failure of the severed axons to regenerate. Restoration of function depends on overcoming endogenous obstacles to regeneration, and re-establishing neural connections across the lesion site. Recent research indicates that multiple factors - the trophic environment within the CNS, the inhibitory nature of myelin debris and the glial scar, secondary damage, cavitation within the spinal cord, and even the responsive state of the injured neuronal population - all contribute to the failure to regenerate. Although studies that target individual components have had limited success in coaxing some axonal growth across or around lesion sites, it is increasingly clear that no single molecule or mechanism is responsible for the lack of regeneration within the CNS. In addition, research on the development of the nervous system reveal that a variety of guidance cues help growing axons locate and form synapses with their appropriate targets. Families of diffusible and contact-mediated attractant and repellant molecules, and their receptors, are being discovered in worms, flies and mammals, and the intracellular signaling cascades mediating their activities are being identified. In addition, new studies on synaptogenesis implicate the unique roles of organizing molecules, such as nARIA, agrin, gephyrin, PSD95, GRIP and other proteins with PDZ domains that act to recruit and assemble the synaptic apparatus at appropriate sites. These and other exciting results from development need to be brought to bear on the study of SCI. Compared to embryogenesis, however, regeneration poses unique challenges. The mature CNS must adopt new strategies that can operate within the confines of damaged or scarred neural architecture. Successful regeneration may require navigation through foreign or inappropriate terrain within the mature nervous system, and novel reorganization of circuits. Accomplishing these goals may involve the selective reactivation of signaling molecules and mechanisms that operate primarily in embryogenesis. Objectives and Scope This RFA seeks proposals from investigators who study navigational cues that regulate neurite outgrowth and synaptogenesis in development, to apply their findings to the task of re-establishing functional connectivity in the damaged spinal cord. Areas of interest include: O Studies to determine the presence in normal and injured adult spinal cord of guidance molecules or other molecular signals, within growing axons, the axonal environment or target areas that are known to influence neurite outgrowth and synapse formation during development. O Studies to determine the responsiveness of different classes of regenerating axons in the mature spinal cord to trophic factors, guidance molecules, and mechanisms of target selection. O Studies on the synergism of multiple trophic factors and/or extracellular matrices in promoting and guiding axonal regeneration and collateral sprouting within damaged and undamaged regions of the mature spinal cord. O Examination of synaptogenesis within the normal and injured adult spinal cord the classes of synapses formed, the accuracy of re- connectivity, the mechanism and specificity of action of agents, such as trophic factors and small molecules, that regulate synapse re- formation. O Studies on the role of glia and other support cells in the normal maintenance of spinal tracts as well as in regeneration following injury. O Development of improved and versatile implantable materials and cell lines to facilitate the growth of regenerating axons over and beyond the lesion site. O The translation of results obtained from studies on rodents to larger mammals where the dimensions of the spinal cord and requirements for regeneration more closely mimic the situation in human patients. SPECIAL REQUIREMENTS The NINDS invites applications for R21 grants to extend new findings in development to promote regeneration in the mature CNS. The purpose of this RFA is to encourage collaboration between developmental neuroscientists and investigators in the spinal cord field in applying cellular and molecular insights from development to the understanding and eventual treatment of SCI. For this announcement, the R21 mechanism will have a cap of $150,000 direct costs and a maximum term of 3 years. The purpose of this RFA is to encourage new collaborations in spinal cord injury research. It offers an opportunity for young investigators, as well as researchers established in other disciplines, to begin to address problems in SCI, and to generate preliminary data in this new enterprise. Of particular interest are proposals with in vivo models of spinal cord injury in mature mammals that will yield potential strategies to improve regeneration and eventual functional recovery within the adult spinal cord. Collaborations may take the form of sharing of personnel (i.e. research fellows), resources, animal models, and facilities. Travel for investigators to accomplish such collaborations should be budgeted in the applications. Meetings with NINDS staff to discuss progress and share information will be planned separately from the RFA. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) R21, Individual Exploratory/ Developmental Research Grant, award mechanism. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. The total project period for an application submitted in response to this RFA may not exceed three years. This RFA is a one-time solicitation. Future unsolicited competing continuation applications will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. The anticipated award date is July 1, 2001. FUNDS AVAILABLE The NINDS will allocate up to $2.0 million in total costs to support grants in FY 2001. It is anticipated that between 8 and 10 grants may be awarded at an annual direct cost level of $150,000. Applicants may request up to three years of support. In all cases, facilities and administrative (indirect) costs will be awarded based on the negotiated rates. Because the nature and scope of the research proposed may vary, it is anticipated that the size of each award will also vary. Although the financial plans of NINDS 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. ELIGIBILITY REQUIREMENTS Applications may be submitted by foreign or domestic, 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 concerning this RFA are strongly 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, NINDS Neuroscience Center, Room 2209, MSC 9525 6001 Executive Boulevard Bethesda, MD 20892-9525 Telephone: 301-496-1447 FAX: 301-480-1080 Email: ac207q@nih.gov Direct inquiries regarding fiscal matters to: Rita Rollins-Hickey Grants Management Specialist Grants Management Branch, DER, NINDS Neuroscience Center, Room 3249, MSC 9537 Telephone: (301) 496-9231 FAX: 301-402-0219 Email: rr46w@nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by August 15, 2000, a Letter of Intent that includes a descriptive title of the proposed research, the name, address, and telephone number of the Principal Investigator, the identities of other key personnel or participating institutions, and the 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 Institute staff to estimate the potential review workload and avoid conflict of interest in the review. The Letter of Intent is to be sent to: Arlene Y. Chiu, Ph.D. Program Director, Repair and Plasticity National Institute of Neurological Disorders and Stroke National Institutes of Health Neuroscience Center, Room 2202, MSC 9525 6001 Executive Boulevard Bethesda, MD 20892-9525 Rockville, MD 20852 (for courier service) FAX: 301-480-1080 SCHEDULE SUMMARY Letter of Intent Receipt Date: August 15, 2000 Application Receipt Date: October 11, 2000 Peer Review Date: March 2001 Council Review: May 24-25, 2001 Earliest Anticipated Start Date: July 1, 2001 APPLICATION PROCEDURES The Research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants. These forms are available at most institutional offices of sponsored research, from the Division of Extramural Outreach and Information Resources, National Institutes of Health 6701 Rockledge Drive, Room MSC 7910, Bethesda, MD 20892, telephone 301/710-0267, email: GrantsInfo@nih.gov. The RFA label available in the PHS (rev. 4/98) 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 sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf has been modified to allow for this change. Please note this is in pdf format. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS PHS 398 Budget Instructions Modular Grant applications will request direct costs in $25,000 modules, up to a total direct cost request of $150,000 per year. 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: o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $150,000) 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 key 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 key 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. 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: Dr. Lillian M. Pubols Chief, Scientific Review Branch, NINDS, NIH Neuroscience Center, Suite 3208, MSC 9529 6001 Executive Boulevard Bethesda, MD 20892-9529 Rockville, MD 20852 (for express, courier service) Applications must be received by the receipt date designated in this announcement. 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by CSR and responsiveness by NINDS. Incomplete applications will be returned to the applicant without further consideration. Applications will be reviewed for scientific and technical merit by a review group convened by the Scientific Review Branch, NINDS. As part of the initial merit review, all applications will receive a written critique, undergo a process in which only those applications deemed to have the highest scientific merit (generally the top half of the applications received for review) will be discussed, assigned a priority score, and receive a second level review by the NINDS Advisory Council. REVIEW CRITERIA FOR RESEARCH GRANT APPLICATIONS: The R21 mechanism for exploratory/developmental studies was chosen for this RFA to encourage young investigators and investigators not currently engaged in spinal cord injury research to enter the field. Since new avenues are to be explored, extensive preliminary data specific to spinal cord injury may not necessarily be a part of the application, however, the significance of the work, approach to the selected study, and qualifications of the investigators should be apparent. Reviewers will concentrate on the potential of the proposed project to provide information on axonal regrowth and synaptogenesis in the adult spinal cord that can lead to new directions for spinal cord injury research. 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 review, comments on the following aspects of the application will be made 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 the assignment of the overall score. (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? In addition to the above criteria, in accordance with NIH policy, applications will also be reviewed with respect to the following: o The reasonableness of the proposed budget and duration in relation to the proposed research. o The adequacy of the proposed protection for animals and the environment, to the extent they may be adversely affected by the project proposed in the application. AWARD CRITERIA Funding decisions will be based on scientific and technical merit as determined by the Initial Review Group, Program balance and need, review by the National Advisory Neurological Disorders and Stroke Council, and the availability of funds. 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 subpopulations must be included in all NIH supported biomedical and behavioral research projects involving human subjects, unless a clear and compelling rationale and justification is provided 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 research involving human subjects should read the "NIH Guidelines For Inclusion of Women and Minorities as Subjects in Clinical Research," which was published in the Federal Register of March 28, 1994 (FR 59 14508-14513) and in the NIH Guide For Grants and Contracts, Vol. 23, No. 11, March 18, 1994, available on the web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html 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 may also 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. 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, "Pilot projects for spinal cord injury research," is related to the priority area of unintentional injuries: spinal cord injury. 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. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 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, 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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