PATHOGENESIS AND TREATMENT OF DYSKINESIAS IN PARKINSON"S DISEASE RELEASE DATE: July 18, 2002 PA NUMBER: PAS 02-129 EXPIRATION DATE: November 2, 2005, unless reissued. National Institute of Neurological Disorders and Stroke (NINDS) (http://www.ninds.nih.gov) THIS PA CONTAINS THE FOLLOWING INFORMATION o Purpose of the PA o Research Objectives o Research Scope o Mechanism of Support o Funds Available 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 With this Program Announcement, the National Institute of Neurological Disorders and Stroke (NINDS) invites research grant applications (R01) that address the development and treatment of dopamine-induced dyskinesias, a major complication of current pharmacotherapy of Parkinson"s disease. The purpose of this initiative is to 1) support the study of the pathophysiologic basis of dopamine-induced dyskinesias, and 2) support the study of non- dopaminergic pharmacologic agents for the treatment of dopamine-induced dyskinesias. RESEARCH OBJECTIVES Dyskinesias constitute an important complication of the treatment of Parkinson"s disease (PD). Soon after the recognition that loss of dopaminergic neurons in the substantia nigra is the primary pathophysiologic finding in PD the strategy of dopamine replacement by administration of its precursor, levodopa, quickly became the standard therapy for PD. However, more than half of all patients treated with levodopa or other dopaminergic agonists will subsequently develop dyskinesias after approximately five years. In many cases these treatment-induced complications limit the amount of drug that can be administered and, as a further result, the amount of symptomatic relief that can be obtained. The clinical presentation of dyskinesias may vary significantly. These abnormal, involuntary movements may be choreic or dystonic, they are heterogeneous with respect to affected body part and may be associated with other motor symptoms, and they may be associated with high, low or intermediate blood levels of dopamine. When severe or painful, they limit therapy but when mild they can be well tolerated by patients. However even when mild, it is widely held that the appearance of dyskinesias foreshadows the development of other, more disabling motor complications. Therefore, even mild dyskinesias may lead the treating physician to reduce dopaminergic therapy at the price of increased rigidity for the patient. The pathogenesis of dyskinesias is poorly understood. In several areas the available data are incomplete or in conflict. For instance, dyskinesias may be induced by either dopaminergic agonists or antagonists (levodopa induced or tardive dyskinesias, respectively) and can reflect low or high concentrations of dopamine (dystonia and chorea, respectively). While it is well established that dopamine-induced dyskinesias typically develop after the sustained pulsatile administration of a dopamine agonist to a subject (human or primate) with a significant nigral dopaminergic deficit such as in PD, it is clear that dyskinesias can also develop in subjects with intact nigral dopaminergic systems. Our understanding of the physiologic basis of dopamine-induced dyskinesias is similarly incomplete. According to the current model of the basal ganglia, dopamine-induced dyskinesias should be associated with a particular pattern of altered neuronal firing in the globus pallidus (internal and external segments) and the subthalamic nucleus, however several indirect measures of neuronal activity indicate the opposite pattern. Similarly, lesions in the globus pallidus affect dyskinesias in the opposite pattern than would be predicted by the standard model. Finally, much remains to be learned about the physiologic substrate (the specific neurons and their firing patterns) underlying the induction and resolution of dyskinesias. While PD is conventionally considered a disorder of nigral dopaminergic neurons, the integrated unit of cerebral cortex, basal ganglia and thalamus that is compromised includes many neurotransmitters and neuromodulators. These include glutamate, acetylcholine, adenosine, serotonin, opioids, cannabinoids and their cognate receptors and subtypes. Many of these are specifically associated with pathways that may be up or down regulated in PD and thereby present the opportunity for non-dopaminergic approaches to the therapy of PD and its complications. RESEARCH SCOPE Dyskinesias constitute an important complication of PD in three ways. First, they are intrinsically disabling, second, they limit the symptomatic management of the majority of advanced patients, and third, they highlight the limitations of our current understanding of basal ganglia structure and function. There is a particular need to investigate the pathogenesis, pathophysiology and treatment of dyskinesias in PD patients and primate models. Accordingly, applications are solicited to study the following aspects of dyskinesias in the context of PD: Pathogenesis and pathophysiology o Physiological and functional imaging studies in MPTP-treated primates followed by molecular neuroanatomy to establish the altered circuitry of dyskinesia. o Intraoperative recordings from humans during surgery to alleviate dyskinesias. Treatment o Pre-clinical studies of non-dopaminergic agents in dyskinetic primates, o Development and validation of clinical tools such as a dyskinesia rating scale or a predictor of motor complications*, o Pilot studies of non-dopaminergic agents in dyskinetic Parkinsonian patients*. *It is expected that such studies will also conform to the NINDS Pilot clinical trial grant program announcement (PAR 01 119, http://grants1.nih.gov/grants/guide/pa-files/PAR-01-119.html) and such studies should be submitted under the auspices of PAR 01-119. Potential applicants should be aware that this PAR includes additional review criteria and accordingly, are strongly encouraged to contact NINDS program staff for guidance. In summary, a systematic review of the literature indicates that a set of focused studies on dyskinesias in PD should be undertaken. There is a need to investigate the pathogenesis, pathophysiology and treatment of dyskinesias in PD patients and primate models. The research plan must be soundly developed in the context of the current knowledge/research base, with well- defined and clear objectives. Applicants should elaborate on innovative aspects of the proposed research and special attributes of the resources and environment. MECHANISM OF SUPPORT This PA will use the NIH R01 award mechanism. As an applicant, you will be solely responsible for planning, directing, and executing the proposed project. 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. At this time, it is not known if this PA will be reissued. Any future unsolicited competing continuation applications based on this project will compete with all NIH investigator-initiated applications and be reviewed according to the customary peer review procedures. FUNDS AVAILABLE The NINDS intends to commit approximately $2,400,000 to fund up to 6 new competitive grants in response to this PA over the course of the next three years. Because the nature and scope of the proposed research will vary from application to application, it is anticipated that the size and duration of each award will also vary. Awards pursuant to this PA are contingent upon the availability of funds and the receipt of a sufficient number of meritorious applications. ELIGIBLE INSTITUTIONS You may submit application 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 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. SPECIAL REQUIREMENTS As discussed above (RESEARCH SCOPE), some clinical studies responsive to this PA will be expected to be submitted under the auspices of the NINDS Pilot clinical trial grant program announcement (PAR 01 119, http://grants1.nih.gov/grants/guide/pa-files/PAR-01-119.html). Since such applications must conform to the intent of both program announcements, including the additional review criteria of PAR-01-119, potential applicants are strongly encouraged to contact NINDS program staff for guidance. 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 three areas: scientific/research, peer review, and financial or grants management issues: o Direct your questions about scientific/research issues to: Paul Sheehy, Ph.D. Program Director Neurodegeneration Cluster National Institute of Neurological Disorders and Stroke Neuroscience Center, Rm 2214 6001 Executive Blvd MSC 9525 Bethesda, MD 20892-9525 Phone: 301-496-5680 FAX: 301-480-1080 Email: sheehyp@ninds.nih.gov o Direct your questions about financial or grants management matters to: Chris Ann Davis Grants Management Branch National Institute of Neurological Disorders and Stroke Neuroscience Center, Suite 3290 6001 Executive Blvd MSC 9537 Bethesda, MD 20892-9537 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: davisc@ninds.nih.gov SUBMITTING AN APPLICATION Applications must be prepared using the PHS 398 research grant application instructions and forms (rev. 5/2001). 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. BUDGET: The reasonableness of the proposed budget and the requested period of support in relation to the proposed research. OTHER REVIEW CRITERIA: As discussed above (RESEARCH SCOPE), some clinical studies responsive to this PA will be expected to be submitted under the auspices of the NINDS Pilot clinical trial grant program announcement (PAR 01 119, http://grants1.nih.gov/grants/guide/pa-files/PAR-01-119.html). Since such applications must conform to the intent of both program announcements, including the additional review criteria of PAR-01-119, potential applicants are strongly encouraged to contact NINDS program staff for guidance. 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, 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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