THE ROLE OF PARKIN AND RELATED PROTEINS IN PARKINSON’s DISEASE Release Date: April 24, 2000 RFA: NS-01-005 National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: July 15, 2000 Application Receipt Date: August 17, 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 In response to new research discoveries on parkin in the neurodegeneration of Parkinson’s Disease, the National Institute of Neurological Disorders and Stroke (NINDS) invites qualified investigators to submit grant applications for focused studies of the role of parkin and related proteins in Parkinson’s disease and other neurodegenerative disorders. The overall purpose of this initiative is to support and stimulate focused studies of the role of parkin and related proteins in Parkinson’s and other neurodegenerative diseases to elucidate potential common mechanisms relevant to neurodegeneration. RESEARCH OBJECTIVES Background Parkinson's Disease (PD) is the second most common neurodegenerative disease after Alzheimer's Disease. While Parkinson's symptoms usually appear in the late 40's or 50's, they may manifest as early as the late 20's. Recently, a familial early onset form has been described as Autosomal Recessive Juvenile Parkinsonism (AR-JP), and has been linked to a gene which codes for a protein called parkin. Mutations in the parkin gene have been found in a Japanese family, and also in a Greek family, and it is expected that additional families will demonstrate mutations once more patients have been screened. Like the alpha-synuclein protein, also genetically mutated in Parkinson's Disease, the cellular functions of parkin are unknown. However, unlike synuclein, the structure of the parkin protein gives significant clues to its possible function, including potential roles in the ubiquitin pathway and in gene transcription. The amino terminus of parkin bears sequence homology to ubiquitin, suggesting it may attach to proteins and thereby target them for a variety of cellular destinations, including endosomes, lysosomes, or autophagic vesicles. Additionally, there is a RING finger motif at the carboxy terminal end. Recently, RING-finger motifs have been shown to mediate a step in ubiquitination of proteins destined for degradation by the proteasome in cells, and at least one mutation in parkin (T240-R) is found at the start of the RING finger sequence. Thus, parkin may function as an intermediate in the ubiquitin pathway, controlling levels of other proteins or itself by regulated degradation. In addition to the parkin mutations in AJ-RP, a polymorphism in the ubiquitin carboxy-terminal hydrolase gene (UHC-L1) has been discovered in a very few individuals with PD. It comprises 1-2% of total soluble brain protein and is hypothesized to hydrolyse polymeric ubiquitin to monomeric ubiquitin (deubiquitination, or DUB enzyme). UHC-L1, along with ubiquitin, is found in Lewy bodies. So while the frequency of UHC-L1 mutations are probably very low, it further implicates disturbances in the ubiquitin pathway as potentially pathogenic in different forms of PD. Parkin homologs containing ubiquitin-like sequences and accompanying RING fingers have been identified in a variety of systems, including mouse, Drosophila, C. elegans, and yeast. The RING finger domain in the mouse homolog of parkin (RBCK1) functions as a transcriptional activator, and transcription is abolished when the RING domain is mutated. These studies suggest that the parkin RING finger may directly regulate gene expression. The ubiquitin-like sequence also implicates parkin in genetic transcription - similar to targeting proteins to lysosomes, the ubiquitin sequence may target transcriptional proteins to the nucleus. Although not formally participating in this request for applications, the National Institute of Environmental Health Sciences (NIEHS) is interested in research related environmental factors which affect parkin and will consider funding applications which are in the direct mission of their institute. Although not formally participating in this request for applications, the National Institute on Aging (NIA) maintains a strong interest in supporting studies on the role of mutated proteins in Parkinson’s disease and other neurodegenerative disorders. The following investigations will be considered for this proposal: O More expansive genetic studies on the parkin and UHC-L1 mutations in PD families, including those not yet screened for these mutations. O Creation of parkin models in various animal systems, including mice, flies, etc. to better understand parkin function, including the study of cellular interactions of parkin with other proteins. O Structure/function studies of the RING finger domain in parkin or related PD proteins, including their possible role in ubiquitination. O Role of parkin or related PD proteins as potential transcriptional activators. MECHANISM OF SUPPORT 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 This RFA will use the National Institutes of Health (NIH) regular research grant award mechanism (R01). 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 five (5) 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 earliest anticipated award date is April 1, 2001. FUNDS AVAILABLE The NINDS intends to commit up to $1 million in total costs to fund up to four successful applications in FY 2001 in response to this RFA. Applicants may request up to five years of support. In all cases, Facilities and Administrative (indirect) costs will be awarded based on the negotiated rates. 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. ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non- profit organizations, public and private, such as universities, colleges, hospitals, laboratories, units of State and local governments, and eligible agencies of the Federal government. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. INQUIRIES Inquiries concerning this RFA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding scientific and other application-related issues to: Diane D. Murphy, Ph.D. Program Director National Institute of Neurological Disorders and Stroke National Institutes of Health Neuroscience Center 6001 Executive Blvd., Room 2202 Bethesda, MD 20892-9525 Telephone: 301/496-5680 FAX: 301/480-1080 E-mail: murphyd@ninds.nih.gov Direct inquiries regarding review issues to: Dr. Lillian Pubols Chief, Scientific Review Branch, NINDS, NIH Neuroscience Center, Suite 3208 MSC9529 6001 Executive Blvd. Bethesda, MD 20892-9529 Rockville, MD 20852 (for express/courier service) Telephone: 301/496-9223 Email: pubolsl@ninds.nih.gov Direct inquiries regarding fiscal matters to: Kimberly Pendleton Grants Management Specialist Grants Management Branch, DER, NINDS Neuroscience Center 6001 Executive Blvd., Room 3254 Bethesda, MD 20892-9537 Telephone: (301) 496-9231 FAX: 301-402-0219 EMAIL: kp33e@nih.gov LETTER OF INTENT Prospective applicants are asked to submit, by July 15, 2000 a Letter of Intent that includes a descriptive title, the name, address, telephone number, and email address of the Principal Investigator, the identities of other key personnel and participating institutions, 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 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: Diane D. Murphy, Ph.D. Program Director National Institute of Neurological Disorders and Stroke National Institutes of Health Neuroscience Center 6001 Executive Blvd., Room 2202 Rockville, MD 20852 FAX: 301/480-1080 E-mail: murphyd@ninds.nih.gov SCHEDULE SUMMARY Letter of Intent Receipt Date: July 15, 2000 Application Receipt Date: August 17, 2000 Peer Review Date: December 2000 Council Review: February 2001 Early Anticipated Start Date: April 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, Room MSC 7910, Bethesda, MD 20892, 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. 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. There is a sample RFA label available at: http://grants.nih.gov/grants/funding/phs398/label-bk.pdf. 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 will request direct costs in $25,000 modules, up to a total direct cost request of $250,000 per year. (Applications that request more than $250,000 direct costs in any year must follow the traditional PHS 398 application instructions.)The total direct costs must be requested in accordance with the program guidelines and the modifications made to the standard PHS 398 application instructions described below: PHS 398 o FACE PAGE: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $250,000) and Total Costs [Modular Total Direct plus Facilities and Administrative (F&A) costs] for the initial budget period. Items 8a and 8b should be completed indicating the Direct and Total Costs for the entire proposed period of support. o DETAILED BUDGET FOR THE INITIAL BUDGET PERIOD - Do not complete Form Page 4 of the PHS 398. It is not required and will not be accepted with the application. o BUDGET FOR THE ENTIRE PROPOSED PERIOD OF SUPPORT - Do not complete the categorical budget table on Form Page 5 of the PHS 398. It is not required and will not be accepted with the application. o NARRATIVE BUDGET JUSTIFICATION - Prepare a Modular Grant Budget Narrative page. (See http://grants.nih.gov/grants/funding/modular/modular.htm for sample pages.) At the top of the page, enter the total direct costs requested for each year. This is not a Form page. o Under Personnel, List 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 (3) 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 Pubols Chief, Scientific Review Branch, NINDS, NIH Neuroscience Center, Suite 3208 MSC9529 6001 Executive Blvd. Bethesda, MD 20892-9529 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. 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 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 the 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 out important work that by its nature is not innovative but is essential to move a field forward. (1) Significance: Does this study address an important problem? If the aims of the application are achieved, how will scientific knowledge be advanced? What will be the effect of these studies on the concepts or methods that drive this field? (2) Approach: Are the conceptual framework, design, methods, and analyses adequately developed, well-integrated, and appropriate to the aims of the project? Does the applicant acknowledge potential problem areas and consider alternative tactics? (3) Innovation: Does the project employ novel concepts, approaches or method? Are the aims original and innovative? Does the project challenge existing paradigms or develop new methodologies or technologies? (4) Investigator: Is the investigator appropriately trained and well suited to carry out this work? Is the work proposed appropriate to the experience level of the principal investigator and other researchers (if any)? (5) Environment: Does the scientific environment in which the work will be done contribute to the probability of success? Do the proposed experiments take advantage of unique features of the scientific environment or employ useful collaborative arrangements? Is there evidence of institutional support? 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 have been 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, and is available on the web at: http://grants.nih.gov/grants/guide/notice-files/not94-100.html. NIH POLICY AND GUIDELINES ON THE 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 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 Applications (RFA), "The Role of Parkin and Related Proteins in Parkinson's Disease" is related to the priority area of Neurodegenerative Diseases. 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 Sections 301 and 405 of the Public Health Service Act as amended (42 USC 241 and 284) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Parts 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant 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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