STUDIES INTO THE CAUSES AND MECHANISMS OF DYSTONIA RELEASE DATE: August 27, 2002 PA NUMBER: PA-02-156 EXPIRATION DATE: August 31, 2005 unless reissued. National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov/) National Eye Institute (NEI) (http://www.nei.nih.gov) National Institute of Child Health and Human Development (NICHD) (http://www.nichd.nih.gov/) National Institute on Deafness and Other Communication Disorders (NIDCD) (http://www.nidcd.nih.gov/) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Mechanism(s) of Support o Eligible Institutions o Individuals Eligible to Become Principal Investigators o Special Requirements o Where to Send Inquiries o Submitting an Application o Peer Review Process o Review Criteria o Award Criteria o Required Federal Citations PURPOSE OF THIS PA Dystonia is defined clinically as involuntary, often sustained, co- contraction of agonist and antagonist muscles causing abnormal and often painful postures or movements. It is generally believed to be centrally mediated. Dystonia occurs due to many different etiologies. Although the prevalence and disease burden of this group of disorders is not well known, it is estimated by some sources that this debilitating movement disorder affects over 500,000 individuals in the USA. Some forms of dystonia are associated with specific genetic and/or environmental risk factors, but the underlying pathophysiological pathways remain elusive. The purpose of this program announcement is to solicit applications for new studies on the underlying causes of human dystonia, secondary consequences of these movement disorders, and potential therapeutic strategies for treating these conditions. RESEARCH OBJECTIVES Dystonia is the third most common movement disorder. Manifestations can be focal, including spasmodic torticollis (cervical dystonia), blepharospasm, spasmodic dysphonia, "writers cramp" and other task specific dystonias. Dystonia can also be generalized, leading to involuntary twisting of the limbs and trunk. Dystonia is defined as "primary" when it occurs in isolation (without other neurologic or medical problems) or as "secondary" when it occurs in conjunction with other neurological diseases and/or environmental insults. Various pathophysiological mechanisms have been suggested to explain the variable onset of dystonia, including a childhood- adolescent window of susceptibility, low penetrance within genetic subtypes, and multiple suspected environmental triggers. Dystonia appears to be a centrally mediated dysregulation of movement resulting from abnormalities in discrete regions of the brain. In some forms of familial dystonia, particular mutations have been identified, which provide additional insights into pathophysiological pathways. Studies in the field of dystonia offer a number of unique perspectives and opportunities in neurology and neuroscience. For example, in many types of dystonia the condition appears to derive from dysfunction rather than degeneration of neurons. Additionally, the familial forms of the disorder for which genetic causes are known have low penetrance (around 30% for most). This suggests that therapies may be able to "reset" neurons to overcome the dysfunction, and/or that modulation of environmental factors may influence the time of onset and/or the severity of the disease. Recent studies indicate that the neurophysiologic basis of dystonia may reflect aberrations of neuronal plasticity, critical in development and motor learning, and hence studies into the dystonias may offer a window into dynamic aspects of neuronal "learning". Research in this complex set of diseases will require coordinated, expanded and informed efforts among neuroscientists, clinical neurologists, and rehabilitation therapists, with access to patient populations, clinical databases, and patient material. Studies that address underlying commonalities among different types of dystonia on the genetic, cellular, and/or clinical level may be of particular value in pursuing some of these goals. The following are typical of research areas targeted by this initiative: o Identification of genetic factors and heritable mechanisms associated with dystonia, including new gene discovery, causes of variable penetrance, multigene interactions, and studies of other potential molecularly based disease-modifying factors o Identification of proteins that interact with dystonia-related cellular factors (genes, proteins) and determination of their coordinated function o Creation and characterization of animal models for studying the pathophysiological basis of dystonia, functional consequences, and potential therapeutic strategies o Determination of the role of environmental factors in inducing cellular/neurophysiologic changes associated with dystonia and dystonia- related proteins o Studies of abnormalities in both plasticity and motor learning mechanisms that are relevant to dystonias o Development of improved diagnostic and prognostic techniques o Studies into neurophysiological and imaging (e.g., fMRI and TMS) approaches o Studies into the epidemiology of primary and secondary dystonia o Therapeutic strategies in primary and secondary dystonia including both pharmacological and non-pharmacological interventions o Studies into assistive devices, orthotics, and potential accommodations o Studies into environmental risks that cause or exacerbate dystonia o Studies into surgical interventions in dystonia o Studies of non-motor components of dystonia o Studies into the features of pain in dystonia, including how treating pain may affect the underlying disability o Sensory components of dystonia including studies ranging from basic motor- sensory circuitry to dystonia therapy o Studies contrasting the different phenotypes of dystonia (e.g., causes, onset, trajectory, affected muscle groups, level of dysfunction, and other manifestations) in order to gain insight into the pathophysiological mechanisms o Studies into mechanisms, causes, and treatments of dystonia that occurs as a disabling, secondary symptom in neurological diseases such as Parkinson"s disease, Huntington"s disease, tardive dyskinesia/dystonia, and other disorders MECHANISM(S) OF SUPPORT This Program Announcement will use the National Institutes of Health (NIH) research project grant (R01), exploratory developmental research grant (R21), and career development mechanisms (K series). Note that policies on these mechanisms may differ among the sponsoring Institutes, and they may not accept applications that do not conform to specific Institute guidelines. Please contact program staff for Institute specific guidelines, and see the Institute websites as listed below for further details. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. For general information on NINDS funding mechanisms see the guidelines at: http://www.ninds.nih.gov/funding/grant_mechanisms.htm For general information on NEI mechanisms see the guidelines at: http://www.nei.nih.gov/funding/index.htm For general information on NICHD mechanisms see the guidelines at: http://www.nichd.nih.gov/funding/funding-mechs.htm For general information on NIDCD mechanisms see the guidelines at: http://www.nidcd.nih.gov/funding/ This PA uses just-in-time concepts. It also uses the modular as well as the non-modular budgeting formats (see http://grants.nih.gov/grants/funding/modular/modular.htm). Specifically, if you are submitting an application with direct costs in each year of $250,000 or less, use the modular format. Otherwise follow the instructions for non- modular research grant applications. ELIGIBLE INSTITUTIONS You may submit (an) application(s) if your institution has any of the following characteristics: o For-profit or non-profit organizations o Public or private institutions, such as universities, colleges, hospitals, and laboratories o Units of State and local governments o Eligible agencies of the Federal government o Domestic or foreign o Faith-based or community based organizations INDIVIDUALS ELIGIBLE TO BECOME PRINCIPAL INVESTIGATORS Any individual with the skills, knowledge, and resources necessary to carry out the proposed research is invited to work with their institution to develop an application for support. Individuals from underrepresented racial and ethnic groups as well as individuals with disabilities are always encouraged to apply for NIH programs. WHERE TO SEND INQUIRIES We encourage your inquiries concerning this PA and welcome the opportunity to answer questions from potential applicants. Inquiries may fall into two areas: scientific/research and financial or grants management issues. o Direct your questions about scientific/research issues to: Katrina Gwinn-Hardy, M.D. Program Director, Neurogenetics Cluster National Institute of Neurological Disorders and Stroke, NIH 6001 Executive Blvd Room 2142, MSC 9525 Bethesda, MD 20892-9525 Telephone: (301) 496-5745 FAX: (301) 402-1501 Email: gwinnk@ninds.nih.gov Chyren Hunter, Ph.D. Division of Extramural Research National Eye Institute Executive Plaza South, Suite 350 6120 Executive Blvd, MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 451-2020 FAX: (301) 402-0528 Email: clh@nih.gov Ralph M. Nitkin, Ph.D. Program Director, Biological Sciences and Career Development National Center for Medical Rehabilitation Research National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 2A03, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 402-2242 FAX: (301) 402-0832 Email: rn21e@nih.gov Lana Shekim, Ph.D. Program Director, Voice and Speech Scientific Programs Branch, DER National Institute on Deafness and Other Communication Disorders, NIH 6120 Executive Blvd, EPS-400-C MSC 7180 Bethesda MD 20892-7180 Telephone: (301) 402-0832 Fax: (301) 402-6251 Email: shekiml@nidcd.nih.gov o Direct your questions about financial or grants management matters to: Kathleen A. Howe Grants Management Branch National Institute of Neurological Disorders and Stroke, NIH 6001 Executive Blvd., Rm. 3290, MSC 9537 Bethesda, MD 20892-9537 Telephone: (301)496-9231 Fax: (301)402-0219 Email: kh52x@nih.gov William W. Darby Grants Management Officer National Eye Institute Executive Plaza South, Suite 350 6120 Executive Blvd, MSC 7164 Bethesda, MD 20892-7164 Telephone: (301) 496-5884 FAX: (301) 496-9997 Email: wwd@nei.nih.gov Christopher Myers Grants Management Branch National Institute of Child Health and Human Development 6100 Executive Boulevard, Room 8A17H, MSC 7510 Bethesda, MD 20892-7510 Telephone: (301) 496-6996 FAX: (301) 480-4782 Email: cm143g@nih.gov Sara Stone Chief, Grants Management Branch National Institute of Deafness and Other Communication Disorders 6120 Executive Boulevard, Room 400B, MSC 7180 Bethesda MD 20892-7180 Telephone: (301) 402-0909 FAX: (3010) 402-1758 Email: stones@nidcd.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). Specific instructions for the R21 and K mechanisms can be found on the appropriate Institute websites as listed above. The PHS 398 is available at http://grants.nih.gov/grants/funding/phs398/phs398.html in an interactive format. For further assistance contact GrantsInfo, Telephone (301) 435-0714, Email: GrantsInfo@nih.gov. APPLICATION RECEIPT DATES: Applications submitted in response to this program announcement will be accepted at the standard application deadlines, which are available at http://grants.nih.gov/grants/dates.htm. Application deadlines are also indicated in the PHS 398 application kit. SPECIFIC INSTRUCTIONS FOR MODULAR GRANT APPLICATIONS: Applications requesting up to $250,000 per year in direct costs must be submitted in a modular grant format. The modular grant format simplifies the preparation of the budget in these applications by limiting the level of budgetary detail. Applicants request direct costs in $25,000 modules. Section C of the research grant application instructions for the PHS 398 (rev. 5/2001) at http://grants.nih.gov/grants/funding/phs398/phs398.html includes step-by-step guidance for preparing modular grants. Additional information on modular grants is available at http://grants.nih.gov/grants/funding/modular/modular.htm. SPECIFIC INSTRUCTIONS FOR APPLICATIONS REQUESTING $500,000 OR MORE PER YEAR: Applications requesting $500,000 or more in direct costs for any year must include a cover letter identifying the NIH staff member within one of NIH institutes or centers who has agreed to accept assignment of the application. Applicants requesting more than $500,000 must carry out the following steps: 1) Contact the IC program staff at least 6 weeks before submitting the application, i.e., as you are developing plans for the study, 2) Obtain agreement from the IC staff that the IC will accept your application for consideration for award, and, 3) Identify, in a cover letter sent with the application, the staff member and IC who agreed to accept assignment of the application. This policy applies to all investigator-initiated new (type 1), competing continuation (type 2), competing supplement, or any amended or revised version of these grant application types. Additional information on this policy is available in the NIH Guide for Grants and Contracts, October 19, 2001 at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-004.html. SENDING AN APPLICATION TO THE NIH: 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) APPLICATION PROCESSING: Applications must be received by or mailed on or before the receipt dates described at http://grants.nih.gov/grants/funding/submissionschedule.htm. The CSR will not accept any application in response to this PA 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 a substantial revision of an application already reviewed, but such application must include an Introduction addressing the previous critique. PEER REVIEW PROCESS Applications submitted for this PA will be assigned on the basis of established PHS referral guidelines. An appropriate scientific review group convened in accordance with the standard NIH peer review procedures (http://www.csr.nih.gov/refrev.htm) will evaluate applications for scientific and technical merit. As part of the initial merit review, all applications will: o Receive a written critique o Undergo a selection process in which only those applications deemed to have the highest scientific merit, generally the top half of applications under review, will be discussed and assigned a priority score o 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 your application in order to judge the likelihood that the proposed research will have a substantial impact on the pursuit of these goals: o Significance o Approach o Innovation o Investigator o Environment The scientific review group will address and consider each of these criteria in assigning your application"s overall score, weighting them as appropriate for each application. Your application does not need to be strong in all categories to be judged likely to have major scientific impact and thus deserve a high priority score. For example, you may propose to carry out important work that by its nature is not innovative but is essential to move a field forward. (1) SIGNIFICANCE: Does your study address an important problem? If the aims of your application are achieved, how do they advance scientific knowledge? What will be the effect of these studies on the concepts or methods that drive this field? (2) APPROACH: Are the conceptual framework, design, methods, and analyses adequately developed, well integrated, and appropriate to the aims of the project? Do you acknowledge potential problem areas and consider alternative tactics? (3) INNOVATION: Does your project employ novel concepts, approaches or methods? Are the aims original and innovative? Does your project challenge existing paradigms or develop new methodologies or technologies? (4) INVESTIGATOR: Are you appropriately trained and well suited to carry out this work? Is the work proposed appropriate to your experience level as the principal investigator and to that of other researchers (if any)? (5) ENVIRONMENT: Does the scientific environment in which your work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? ADDITIONAL REVIEW CRITERIA: In addition to the above criteria, your application will also be reviewed with respect to the following: PROTECTIONS: The adequacy of the proposed protection for humans, animals, or the environment, to the extent they may be adversely affected by the project proposed in the application. INCLUSION: The adequacy of plans to include subjects from both genders, all racial and ethnic groups (and subgroups), and children as appropriate for the scientific goals of the research. Plans for the recruitment and retention of subjects will also be evaluated. (See Inclusion Criteria included in the section on Federal Citations, below) DATA SHARING: The adequacy of the proposed plan to share data when such a plan is appropriate for the area of study. Contact the program official for discussion if needed. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. AWARD CRITERIA Applications submitted in response to a PA will compete for available funds with all other recommended applications. The following will be considered in making funding decisions: o Scientific merit of the proposed project as determined by peer review o Availability of funds o Relevance to program priorities REQUIRED FEDERAL CITATIONS MONITORING PLAN AND DATA SAFETY AND MONITORING BOARD: Research components involving Phase I and II clinical trials must include provisions for assessment of patient eligibility and status, rigorous data management, quality assurance, and auditing procedures. In addition, it is NIH policy that all clinical trials require data and safety monitoring, with the method and degree of monitoring being commensurate with the risks (NIH Policy for Data Safety and Monitoring, NIH Guide for Grants and Contracts, June 12, 1998: http://grants.nih.gov/grants/guide/notice-files/not98-084.html). INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH: It is the policy of the NIH that women and members of minority groups and their sub-populations must be included in all NIH-supported clinical research projects unless a clear and compelling justification is provided indicating that inclusion is inappropriate with respect to the health of the subjects or the purpose of the research. This policy results from the NIH Revitalization Act of 1993 (Section 492B of Public Law 103-43). All investigators proposing clinical research should read the AMENDMENT "NIH Guidelines for Inclusion of Women and Minorities as Subjects in Clinical Research - Amended, October, 2001," published in the NIH Guide for Grants and Contracts on October 9, 2001 (http://grants.nih.gov/grants/guide/notice- files/NOT-OD-02-001.html), a complete copy of the updated Guidelines are available at http://grants.nih.gov/grants/funding/women_min/guidelines_amended_10_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: The NIH maintains a policy that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. This policy applies to all initial (Type 1) applications submitted for receipt dates after October 1, 1998. All investigators proposing research involving human subjects should read the "NIH Policy and Guidelines" on the inclusion of children as participants in research involving human subjects that is available at http://grants.nih.gov/grants/funding/children/children.htm. REQUIRED EDUCATION ON THE PROTECTION OF HUMAN SUBJECT PARTICIPANTS: NIH policy requires education on the protection of human subject participants for all investigators submitting NIH proposals for research involving human subjects. You will find this policy announcement in the NIH Guide for Grants and Contracts Announcement, dated June 5, 2000, at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-00-039.html. HUMAN EMBRYONIC STEM CELLS (hESC): Criteria for federal funding of research on hESCs can be found at http://grants.nih.gov/grants/stem_cells.htm and at http://grants.nih.gov/grants/guide/notice-files/NOT-OD-02-005.html. Only research using hESC lines that are registered in the NIH Human Embryonic Stem Cell Registry will be eligible for Federal funding (see http://escr.nih.gov). It is the responsibility of the applicant to provide the official NIH identifier(s)for the hESC line(s)to be used in the proposed research. Applications that do not provide this information will be returned without review. PUBLIC ACCESS TO RESEARCH DATA THROUGH THE FREEDOM OF INFORMATION ACT: The Office of Management and Budget (OMB) Circular A-110 has been revised to provide public access to research data through the Freedom of Information Act (FOIA) under some circumstances. Data that are (1) first produced in a project that is supported in whole or in part with Federal funds and (2) cited publicly and officially by a Federal agency in support of an action that has the force and effect of law (i.e., a regulation) may be accessed through FOIA. It is important for applicants to understand the basic scope of this amendment. NIH has provided guidance at http://grants.nih.gov/grants/policy/a110/a110_guidance_dec1999.htm. Applicants may wish to place data collected under this PA in a public archive, which can provide protections for the data and manage the distribution for an indefinite period of time. If so, the application should include a description of the archiving plan in the study design and include information about this in the budget justification section of the application. In addition, applicants should think about how to structure informed consent statements and other human subjects procedures given the potential for wider use of data collected under this award. URLs IN NIH GRANT APPLICATIONS OR APPENDICES: All applications and proposals for NIH funding must be self-contained within specified page limitations. Unless otherwise specified in an NIH solicitation, Internet addresses (URLs) should not be used to provide information necessary to the review because reviewers are under no obligation to view the Internet sites. Furthermore, we caution reviewers that their anonymity may be compromised when they directly access an Internet site. HEALTHY PEOPLE 2010: The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2010," a PHS-led national activity for setting priority areas. This PA 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 (NINDS), 93.867 (NEI), 93.929 (NICHD), and 93.173 (NIDCD), and is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. Awards are made under authorization of Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284 and administered under NIH grants policies described at http://grants.nih.gov/grants/policy/policy.htm and under Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. The PHS strongly encourages all grant recipients to provide a smoke-free workplace and discourage the use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, any portion of a facility) in which regular or routine education, library, day care, health care, or early childhood development services are provided to children. This is consistent with the PHS mission to protect and advance the physical and mental health of the American people.
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