THE ROLE OF THE ENVIRONMENT IN PARKINSON'S DISEASE Release Date: September 21, 1999 RFA: ES-00-002 National Institute of Environmental Health Sciences National Institute of Neurological Disorders and Stroke Letter of Intent Receipt Date: November 5, 1999 Application Receipt Date: January 11, 2000 THIS RFA USES THE "MODULAR GRANT" AND "JUST-IN-TIME" CONCEPTS. IT INCLUDES DETAILED MODIFICATIONS TO STANDARD APPLICATION INSTRUCTIONS THAT MUST BE USED WHEN PREPARING APPLICATIONS THAT ARE RESPONDING TO THIS RFA. PURPOSE The objective of this Request for Applications (RFA) is to stimulate research on the relative roles of environmental, endogenous neurochemical and modifying genetic factors in the cause of Parkinson's disease. Recent evidence from twin studies has shown that genetics plays less of a role and environmental factors a potentially greater role than previously thought in the development of late-onset Parkinson's disease (PD). In response to this finding, the National Institute of Environmental Health Sciences (NIEHS) and National Institute of Neurological Disorders and Stroke (NINDS) invites scientists to submit research grant applications for research aimed at elucidating the role of the environment in the development of Parkinson's disease. The results of these investigations will contribute to clarifying the part environmental factors play in the etiology of this disease. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention objectives of "Healthy People 2000," a PHS-led national activity for setting priority areas. This RFA, "The Role of the Environment in Parkinson's Disease," is related to one or more of the priority areas. Potential applicants may obtain a copy of "Healthy People 2000" at http://odphp.osophs.dhhs.gov/pubs/hp2000 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. FUNDS AVAILABLE The total estimated funds available for support of the research project grant (R01, R21) award mechanisms in this Request for Applications are $4,000,000 per year. This level of expenditure is contingent upon the receipt of a sufficient number of applications directly relevant to the objectives of this RFA that are of high scientific quality as judged by a peer-review merit evaluation and the actual available funds. MECHANISM OF SUPPORT This RFA will use the National Institutes of Health (NIH) research project grant (R01, R21) award mechanisms. The R01 grant mechanism supports a discrete, specified, circumscribed research project that is well-grounded on current knowledge and to be performed by the named investigator(s) in an area of research representing his/her/their specific interest and competencies. The R21 is an exploratory/developmental grant mechanism that supports the development of new research activities in categorical program areas with more restricted levels of time and funding. For R21s, a maximum of $100,000 (four $25,000 modules) per year for a maximum of two years will be allowed. For R01s, applications requesting up to $250,000 direct cost must be submitted in the modular grant format. R01 applications requesting budgets greater than $250,000 must submit detailed budget information with the application. The total project period for an application submitted in response to this RFA may not exceed two years for an R21 or five years for an R01. Responsibility for the planning, direction, and execution of the proposed project will be solely that of the applicant. For administrative reasons, the primary assignment of all applications will initially be to the NIEHS. After discussion with the other participating Institute programs, applications may be reassigned where they are programmatically most appropriate. Background While much of the previous research in Parkinson's disease (PD) has focused on the underlying biological processes critical to disease manifestation in the hopes of developing new treatments, the relative roles of environmental, endogenous neurochemical and modifying genetic factors in the causation of neurodegenerative diseases remain unclear. For example, it is not clear whether differences in prevalence rates of PD in various communities are due to the differential distribution of a hypothetical environmental toxicant or are more frequent where a heritable defect is more common. Moreover, analytic epidemiological studies have varied in case and control selection methodology and venues (e.g., clinics, population bases, different countries) partly accounting for the disparate conclusions reached by investigators. New evidence from a recent study showed that there was no statistically significant difference in the incidence of late-onset (over the age of 50) PD between monozygotic and dizygotic twins. This finding indicates a potentially greater role for environmental agents in the etiology of the disease than previously appreciated. However, the relative roles of genetic susceptibility and environmental factors in triggering PD remain to be determined. The observation that cigarette smoking appears to protect against the development of PD illustrates the complex role that exogenous agents play in the development of PD. Other epidemiological studies have implicated pesticide exposure and rural living as risk factors for developing PD. New evidence has emerged from one study showing that long-term occupational exposure to certain combinations of metals is significantly associated with developing PD. This is the first study to link a 20- year or more occupational exposure to heavy metals with a chronic neurodegenerative disorder. The study also found a link to PD and occupational exposure to herbicides, insecticides and farming. Findings from research using animal models and in vitro techniques have begun to support some of these epidemiological findings. For example, a study in mice investigating the role of organochlorine pesticides in altering normal dopaminergic function has led to the observation that the pesticide, heptachlor significantly inhibits vesicular uptake of dopamine making the striatal neurons more vulnerable to degeneration. RESEARCH OBJECTIVES The National Institute of Environmental Health Sciences convened a Concept Forum on the Role of the Environment in Parkinson's Disease on July 22, 1999 to evaluate the current evidence and identify future research needs in three areas: basic research, epidemiological research, and clinical research. The Forum concluded that elucidating the role of the environment in the etiology of PD is important in developing a better understanding of the disease process for both its prevention and treatment. Therefore, applications are solicited in, but not limited to, the following areas: - Research aimed at understanding the mechanism by which environmental exposure, endogenous susceptibility factors, and increasing age contribute to the etiopathology of PD. Of particular significance may be those approaches that can be used across species from lower animals to humans. Such approaches permit a precise characterization in animal models of alterations arising from defined environmental exposures which can serve as a cogent guide to underlying cellular and molecular mechanisms necessary to support epidemiological studies. - Epidemiological studies targeted to specific environmental agents and/or combination of factors associated with an increased risk for neurodegenerative disorders. These studies may target populations already characterized in terms of the incidence and risks for neurodegenerative diseases (e.g., farmers with significant exposure to pesticides) and should use advanced techniques in exposure assessment as well as biomarkers of exposure and effect when possible. - Development of biomarkers of preclinical disease to identify those at risk for selected environmental toxicants, and to identify those who would benefit from trials of possibly neuroprotective drugs. - Studies focusing on early disease which help clarify the contributions and attributable risks from environmental or gene/environmental interactions. - Studies developing models of neurodegenerative disease from low-level and/or chronic exposure to environmental agents and synergistic chemical interactions leading to neuronal injury. - Development of genetically modified transgenics or knockout animals to study increased susceptibility to environmentally induced neurodegeneration and the efficacy of therapeutic interventions. - Elucidation of gene-environment interactions using molecular epidemiology tools. - Studies of the cellular and molecular effect of environmental toxins on alterations in oxidative stress, increased mitochondrial mutations and dysfunction and altered protein metabolism including the metabolism of ?-synuclein and parkin. - Toxicant-induced paradigms for studying the mechanism of formation and the role of Lewy body and Lewy body-like inclusions and the comparisons of these structures with those seen in idiopathic PD. - Studies on the role of inflammatory processes in toxicant-induced PD. - Xenobiotics' potential influence on programmed cell death, neural plasticity, or other processes critical to the maintenance of neuronal viability and function. - Potential role of dietary and life style factors, e.g., fat, fiber, iron, antioxidants, alcohol, caffeine, and tobacco as either predisposing or preventive influences. - Studies on the disruption of dopamine function in the substantia nigra by environmental contaminants. Applications that are collaborations between basic, clinical neuroscientists, and neurotoxicologists and/or interdisciplinary in nature are especially encouraged. 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 sub populations 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 available on the web at the following URL address: http://grants.nih.gov/grants/guide/notice-files/not94-100.html INCLUSION OF CHILDREN AS PARTICIPANTS IN RESEARCH INVOLVING HUMAN SUBJECTS It is the policy of NIH that children (i.e., individuals under the age of 21) must be included in all human subjects research, conducted or supported by the NIH, unless there are scientific and ethical reasons not to include them. 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. LETTER OF INTENT Prospective applicants are asked to submit a letter of intent that includes a descriptive title of the proposed research, the name, address, and telephone and facsimile numbers of the Principal Investigator, the identities of other key personnel and participating institutions, and the number and title of this RFA. Although a letter of intent is not required and is not binding, and does not enter into the review of a subsequent application, providing it is highly encouraged. The information it contains will allow NIH staff to estimate the workload and avoid potential conflicts of interest in the review process planning. The letter of intent is to be sent by to Dr. Linda Bass at the NIEHS at the address given below by the letter of intent receipt date listed at the heading of this RFA. 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 301/435-0714, email: GrantsInfo@nih.gov. They may also be downloaded from the Internet at: http://grants.nih.gov/grants/funding/phs398/phs398.html Specific application instructions for this RFA have been modified to reflect "MODULAR GRANT" and "JUST-IN-TIME" streamlining efforts being offered 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 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. Please note, however, that the Principal Investigator should be prepared to budget for travel funds up to $2000 to attend an annual meeting of the grantees if an award is made. The meeting will be coordinated by NIEHS/NINDS Program Officials for the express purpose of sharing research progress and goals. 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. In preparing Modular Grant Applications, the standard instructions for specific award mechanisms should be generally followed: (R01 and R21), with these specific modifications reflecting modular budget and just-in-time concepts: Modular Grant applications must 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 PHS398 application instructions and not be formatted as a modular grant application. The total direct costs must be requested in accordance with the program guidelines for the individual R01 or R21 mechanism described in this RFA. The formatting must follow the modifications made to the standard PHS 398 application instructions described below: o Face Page: Items 7a and 7b should be completed, indicating Direct Costs (in $25,000 increments up to a maximum of $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. Provide an additional narrative budget justification for any variation in the number of modules requested. o Personnel - 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. o Consortium/Contract Costs - 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. 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, for ongoing research projects and those completed during the last three years, and - list selected peer-reviewed publications, with full citations. o Other Support - Do not submit the 'other support' pages. Selected other support relevant to the proposed research may be included in the Biographical Sketch as indicated above. Complete other support information will be requested by the staff of NIEHS or collaborating Institutes if there is a possibility for an award. o Checklist - This page should be completed and submitted with the application. If an 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 Page Limitation - Page limitations for the R01 applications are as stated for the PHS 398 instructions for this mechanism. In keeping with the exploratory/development nature of the R21 mechanism, the application (aims, background and significance, preliminary data and experimental design and methods) is limited to 20 pages. Tables and figures are included in the 20-page limitation. o Appendix - An appendix or additional supporting materials will not be accepted with the exception of originals of photos used in the application. o Contact - 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. o RFA Label - 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. RFA number on label. 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. Submit a signed, typewritten original of the application, including the Checklist, and three signed photocopies, in one package to: CENTER FOR SCIENTIFIC REVIEW NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040, MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for express/courier service) At the time of submission, two additional copies of the application must be sent to: Linda K. Bass, Ph.D. Scientific Review Administrator Scientific Review Branch Division of Extramural Research & Training National Institute of Environmental Health Sciences PO Box 12233, MD EC-24 Research Triangle Park, NC 27709 Telephone: (919) 541-1307 Fax: (919) 541-2503 email: bass@niehs.nih.gov REVIEW CONSIDERATIONS Upon receipt, applications will be reviewed for completeness by the CSR and responsiveness by the NIH. Incomplete and/or non-responsive applications will be returned to the applicant without further consideration. An appropriate peer review group convened by the NIEHS in accordance with the review criteria stated below will evaluate applications that are complete and responsive to the RFA for scientific and technical merit. As part of the initial merit review, a process may be used by the initial review group in which applications 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 and assigned a priority score. The scored applications will receive a second level review by the Institutes 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: 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. The reasonableness of the proposed budget and duration in relation to the proposed research. 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. The initial review group will also examine the provisions for the protection of human subjects and the safety of the research environment. SCHEDULE Letter of Intent Receipt Date: November 5, 1999 Application Receipt Date: January 11, 2000 Peer Review Date: March, 2000 Council Review: May, 2000 Earliest Anticipated Start Date: July 1, 2000 AWARD CRITERIA Award criteria that will be used to make award decisions include: o Scientific merit (as determined by peer review); o programmatic priorities, and o availability of funds. INQUIRIES Inquiries are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Direct inquiries regarding R01 and R21 programmatic issues to: Annette G. Kirshner, Ph.D. Division of Extramural Research and Training National Institute of Environmental Health Science Box 12233, MD EC-23 Research Triangle Park, NC 27709 Telephone: (919) 541-0488 FAX: (919) 541-5064 Email: kirshner@niehs.nih.gov Eugene J. Oliver, Ph.D. Division of Stroke, Trauma and Neurodegenerative Disorders National Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 806 Bethesda, MD 20892 Telephone: (301) 496-5680 FAX: (301) 480-1080 Email: eo11c@nih.gov Direct inquiries regarding fiscal matters to: Dorothy G. Duke Division of Extramural Research and Training National Institute of Environmental Health Science Box 12233, MD EC-22 Research Triangle Park, NC 27709 Telephone: (919) 541-2749 FAX: (919) 541-2860 Email: mineo@niehs.nih.gov Mary Graham Grants Management Branch National Institute of Neurological Disorders and Stroke 7550 Wisconsin Avenue, Room 806 Bethesda, MD 20892 Telephone: (301) 496-9231 FAX: (301) 402-0219 Email: pd23n@nih.gov AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.113 and 93.866. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-158, 42 USC 241 and 285) and administered under NIH grants policies and Federal Regulations 42 CFR 52 and 45 CFR Part 74 and 92. This program is not subject to the intergovernmental review requirements of Executive Order 12372 or Health Systems Agency review. The PHS strongly encourages all grant and contract recipients to provide a smoke-free workplace and promote the non-use of all tobacco products. In addition, Public Law 103-227, the Pro-Children Act of 1994, prohibits smoking in certain facilities (or in some cases, and 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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