INNOVATIONS IN TRANSLATIONAL EPILEPSY RESEARCH FOR JUNIOR INVESTIGATORS Release Date: March 27, 2000 RFA: NS-01-006 National Institute of Neurological Disorders and Stroke http://www.ninds.nih.gov Letter of Intent Receipt Date: October 1, 2000 Application Receipt Date: November 15, 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 The National Institute of Neurological Disorders and Stroke (NINDS) is interested in promoting collaborations among junior investigators (Postdoctoral Fellows through Assistant Professors, or equivalent) to stimulate translational research in the field of epilepsy. This exploratory grants program is being issued in conjunction with the White House-initiated, NIH-sponsored conference, "Curing Epilepsy: Focus on the Future." To this end the NINDS invites exploratory/developmental research grant applications (R21) in patient- oriented research, developmental neurobiology, genetics, advanced technology, imaging, pharmacotherapeutics, or other research areas, which are likely to lead to the cure of epilepsy (defined as "the prevention of epilepsy before it occurs in people at risk, and the cessation of seizures without therapy-associated side effects in those who develop the disease"). Emphasis will be placed on cross- disciplinary collaborations, novel hypotheses, and unique approaches in applying fundamental neurobiological concepts to epilepsy research. Special consideration will be given to proposals that enhance the application of scientific knowledge to the understanding and treatment of the disorder. This initiative requires collaborations of two or more junior investigators at different institutions, or in different laboratories within the same institution. Investigators already working together at the same department are not eligible. RESEARCH OBJECTIVES The purpose of this initiative is to 1) focus attention of young investigators on translational research in epilepsy; 2) promote the interaction of basic researchers and clinical scientists; and 3) provide preliminary information leading to the prevention and cure of epilepsy. The ultimate goal is to effect meaningful advances in understanding the factors that contribute to epileptogenesis, and to develop interventions and effective treatments that improve the quality of life of people with the disorder. Background Epilepsy, characterized by the repeated occurrence of uncontrolled seizures, is one of the most common neurological disorders in our country. It currently afflicts approximately 15 million Americans of all ages and backgrounds. Epilepsy exacts an enormous toll on patients and their families, and has a huge impact on society related to loss of employment potential and the cost of medical care. Despite many decades of research, new anticonvulsant drugs, and advances in surgical therapy, a large number of people with epilepsy suffer from incompletely controlled seizures or the side effects of drugs or surgical treatment. For these patients, current approaches to treatment will, at best, lessen but not prevent the occurrence of seizures. At worst, current therapies cause debilitating side effects and have little or no effect on seizures. In addition, there has been complacency on the part of the medical establishment to accept partial control of seizures, or therapy-associated side effects, as an acceptable, long-term outcome for patients with epilepsy. Research in neuroscience has escalated rapidly in the past decade, especially in the areas of molecular biology, genetics, neuroimaging, and clinical diagnosis. The purpose of this initiative is to apply this knowledge to curing epilepsy. The initiative requires collaborations among two or more junior investigators at different institutions or at different laboratories within the same institution. The intent is to develop innovative proposals in translational epilepsy research. Potential topic areas for proposals may include, but are not limited to: mechanisms for interrupting or modifying the process of epileptogenesis (i.e., approaches aimed at preventing the formation of a seizure focus in patients at risk for epilepsy); identification and characterization of genetic mutations that are the basis of inherited forms of epilepsy and which can provide a means of understanding the causes of seizures and determining treatment strategies; studies of the basic biology of neural development that might contribute to identification of the molecular basis for abnormalities observed in some patients; visualization of structural and functional changes in the brains of patients using advanced imaging technologies such as magnetic resonance spectroscopy, functional magnetic resonance imaging and magnetoencephalography; development of new classes of pharmacological agents and other effective therapeutic strategies such as focal brain stimulation and brain irradiation; and, innovative clinical trial methodologies to quickly identify effective antiepileptogenic interventions. A brief description of the areas of emphasis follows: Interrupting epileptogenesis -- Epilepsy may develop after common brain "insults" including stroke, trauma, prolonged febrile convulsions, meningitis and encephalitis, or in the course of chronic neurodegenerative diseases such as Alzheimer's disease. Being able to identify whether the epilepsy develops when the lesion first occurs, or later when the first seizure appears, will have a major impact on the ability to prevent, or "cure", epilepsy. Animal models of brain injury have shown the progression of anatomic, physiologic and molecular changes that occur; however, there has been little success in preventing the development of epilepsy after injury in these models. Treatment with antiepileptic drugs has failed to prevent epilepsy in patients after head trauma in controlled clinical trials. Grant applications are encouraged that address topics such as brain development, cell loss, neurogenesis, cell migration, axonal or dendritic reorganization, seizure- or injury-induced changes in gene expression, modulation of receptor functions, and other mechanisms that may contribute to altered network function in the CNS. The applications should address how this knowledge can be applied to the formation of better hypotheses about mechanisms of epileptogenesis and better models to test new approaches to prevention. Monitoring epileptogenesis -- Structural brain imaging has been used to identify epileptogenic lesions in patients with seizures and has revolutionized our understanding of the basic mechanisms of epilepsy. The ability to monitor the process of epileptogenesis is an essential component of any approach aimed at preventing epilepsy or treating individuals known to be at high risk for developing epilepsy. Studies are encouraged that address the monitoring of changes in lesions (e.g., tumor growth), anatomy (mesial temporal sclerosis), and electrical activity. Studies that characterize receptors and explain biochemical changes may be able to provide insights into focal and regional pathology that lead to predicting responsiveness to antiepileptic medications. An emerging area of research involves the concept of network synchrony. Neuronal network synchrony increases prior to a seizure and remains elevated for hours following the event. The ability to assess these dynamic changes and apply measurements of neuronal network synchrony to interictal periods and ictal events may help predict, and prevent, seizure occurrence. Genetic strategies -- The epilepsies are a heterogeneous group of disorders with many underlying causes. Recent advances in molecular biology have provided insight into the genetic basis of inherited epilepsies in humans and in model organisms such as the mouse. Epilepsy genes have been found to fall into several distinct categories. Mutations have been identified in genes that encode voltage-gated or ligand-gated ion channels associated with human idiopathic epilepsies. They are predicted to directly or indirectly increase neuronal excitability, which lead to seizures. Mouse mutants, including phenotypes with generalized spike-wave discharges, also provide evidence of epilepsy as an ion channel disease. Mutations in a gene encoding an actin-binding protein that initiates neuronal migration, and two genes that encode possible cell signaling proteins that direct neuronal migration, have been identified in neuronal migration disorders. Other genes involve progressive neurodegeneration and disturbances of cerebral energy metabolism. The exact function of these various genes, and the pathways of which they are a part, remain to be discovered. However, it is expected that further discoveries of genes associated with epilepsy, as well as studies of the mechanisms by which genes cause epilepsy, will substantially advance our understanding of the biological basis of many forms of seizure disorders. This will, in turn, lead to progress in the treatment and cure of patients with epilepsy. Therapeutic strategies -- The goal of curing epilepsy is to identify individuals who are at risk for developing the disorder and to provide effective treatment without therapeutic side effects to those who have the disease. Topics to address may include, but are not limited to: the effectiveness of early pharmacologic interventions in patients presenting with seizures; whether medications may exacerbate long-term problems such as seizure severity and associated cognitive problems; studies to better analyze changes in the CNS of high-risk individuals; evaluation of surgical approaches, including early intervention; alternative therapies such as gene therapy or cell therapy; surrogate markers that can be used to monitor new therapies; and, new designs for intervention studies. Exploratory research studies in this area will hopefully provide the necessary information for determining effective preventative strategies and rational therapeutic designs. Scope and objectives Applications submitted in response to this RFA may address any of the above areas of emphasis. Examples of approaches responsive to this RFA include: o Adaptation of models of neuronal development, injury or degeneration to the study of epilepsy and epileptogenesis. o Novel strategies and hypotheses that enhance understanding of the mechanisms of pathogenesis. o Proposals to identify genes involved in the epilepsies. o Studies directed at the development of therapeutic regimens. This could include identification of appropriate clinical markers (neuroimaging, neurophysiologic, neurochemical), or preliminary information for developing clinical protocols, methodologies, and/or pharmacological agents. o Development of new technologies relevant to the areas of emphasis in this initiative. SPECIAL REQUIREMENTS The research plan should include a section entitled, "Role of Collaborators" (not to exceed three pages) that discusses the contribution of each of the collaborators to the overall effort and how the different parts of the project interact to achieve the proposed goals. The Research Plan must be soundly developed with well-defined and clear objectives. The Approach should make use of appropriate concepts and methodologies. Applicants should elaborate on innovative aspects of the proposed research, novel collaborations, and special attributes of the resources and environment. In addition, applicants must identify how the exploratory studies could result in new insights or capabilities for translational research in epilepsy. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) exploratory/developmental research grant award mechanism (R21). The R21 awards are used for support of creative, novel, and/or high risk/high payoff approaches that could produce innovative advances in this field. This includes feasibility studies, protocol planning, and the incorporation of new disciplines and technologies. This mechanism provides the means to acquire the necessary pilot information, to attract talented new investigators from related disciplines, and to foster the development of interdisciplinary, inter-institutional collaborative efforts among investigators with diverse training and expertise. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. 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 earliest anticipated award date is July 1, 2001. Specific application instructions have been modified to reflect MODULAR GRANT and JUST-IN-TIME streamlining efforts being examined by the NIH. Complete and detailed instructions and information on Modular Grant applications can be found at http://grants.nih.gov/grants/funding/modular/modular.htm. FUNDS AVAILABLE NINDS intends to commit up to $1 million total costs, in FY 2001, to fund new research grants in response to this RFA. An applicant may request a project period of up to three years and a budget for direct costs of up to $150,000 per year. 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 the 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. ELIGIBILTY REQUIREMENTS Applications may be submitted by foreign or domestic, for-profit and nonprofit 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 encouraged. The opportunity to clarify any issues or questions from the potential applicants is welcomed. Direct inquiries regarding programmatic issues to: Margaret P. Jacobs Program Director, Epilepsy Research National Institute of Neurological Disorders and Stroke, NIH Neuroscience Center, Room 2110- 6001 Executive Boulevard Bethesda, MD 20892-9523 Phone: 301/496-1917 Fax: 301/480-2424 Email: mj22o@nih.gov Direct inquiries regarding fiscal matters to: Jerome Lofton Grants Management Branch National Institute of Neurological Disorders and Stroke 6001 Executive Boulevard, Room 3248 Bethesda, MD 20892-9537 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: mj34w@nih.gov LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the names, addresses and telephone numbers of the collaborating investigators, the identities of other key personnel, and the number and title of the RFA in response to which the application may be submitted. Although a letter of intent is not required, is not binding, and does not enter into the review of a subsequent application, the information that it contains allows IC staff to estimate the potential review workload and avoid conflict of interest in the review. The letter of intent is to be sent by October 1, 2000, (fax and e-mail encouraged) to: Margaret P. Jacobs Program Director, Epilepsy Research National Institute of Neurological Disorders and Stroke, NIH Neuroscience Center, Room 2110 6001 Executive Boulevard Bethesda, MD 20892-9523 Phone: 301/496-1917 Fax: 301/480-2424 Rockville, MD 20852 (for express/courier service) Email: mj22o@nih.gov SCHEDULE SUMMARY Letter of Intent Receipt Date: October 1, 2000 Application Receipt Date: November 15, 2000 Peer Review Date: March 2001 Council Review: May 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 and 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. The RFA label available in the PHS 398 (rev. 4/98) application form must be affixed to the bottom of the face page of the application. 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 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 Institute staff. The research grant application form PHS 398 (rev. 4/98) is to be used in applying for these grants, with the modifications noted below. Budget Instructions Modular grant applications in response to this RFA will request direct costs in $25,000 modules, up to a total direct cost of $150,000 per year for up to three years. 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 $150,000 per year) 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, which is not to exceed 3 years. 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 of 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 RESEARCH PLAN: Applications in response to this RFA should include an Introduction, not to exceed 3 pages, as explained above under Research Objectives. This is not included as part of the 25 page limit. 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 time of submission, two additional copies of the application must be sent to: Dr. Lillian Pubols Chief, Scientific Review Branch Division of Extramural Activities, NINDS Neuroscience Center, Room 3208 6001 Executive Blvd. Bethesda, MD 20892 Rockville, MD 20852 (for express/courier service) 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. REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NINDS. 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 NINDS in accordance with the review criteria stated below. 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 NINDS 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 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 important work that by its nature is not innovative but is essential to move a field forward. Given that the purpose of this R21 initiative is to encourage collaborations in translational research in epilepsy, the focus of review will be on innovation in the development of novel concepts, new methodologies, and cross-collaborations. Since the developmental research projects proposed under this RFA may contain preliminary tests of feasibility, substantial risks, and challenges to current concepts, and may lack the amount of preliminary data and background experience normally found in an R01 application, reviewers will weigh the following review criteria accordingly: (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? In the context of the R21 mechanism, a strong rationale and conceptual framework are normally sufficient for establishing the feasibility of the project, in lieu of preliminary data. (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? If the project is not innovative but is essential to move the field forward, the applicant should mention and discuss this aspect in the proposal. (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? (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, 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 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, Volume 23, Number 11, March 18, 1994, and are 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 the 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 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. 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 Request for Application (RFA), Innovations in Translational Epilepsy Research, is related to the priority area of chronic disabling conditions. 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 Federal Domestic Assistance No. Awards are made under authorization of Sections 301 and 405 of the 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, 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 America.


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