Full Text PA-96-050 GENETICS OF PARKINSON'S DISEASE NIH GUIDE, Volume 25, Number 14, May 3, 1996 PA NUMBER: PA-96-050 P.T. 34 Keywords: Genetics Neuromuscular Disorders PURPOSE In response to new basic and clinical developments in Parkinson's disease research and the interest of related voluntary organizations, the Senate Appropriations Subcommittee on Health in 1995 asked the National Institute of Neurological Disorders and Stroke (NINDS) to organize a conference to assess the progress made in Parkinson's disease research, to identify new opportunities and goals, and to plan a research agenda to coordinate and strengthen the cooperative activities of the several NIH institutes supporting research relevant to this disorder. This meeting was held in August 1995 and, with NINDS, was jointly sponsored by the National Institute on Aging, the National Institute of Environmental Health Sciences, and the National Institute of Mental Health. For fiscal year 1996 the Senate Appropriations Committee urged the NINDS to expand its initiatives in areas of promise identified at the August Parkinson's research conference. This Program Announcement (PA) is one of several responses to Congressional interest in this subject. The principal objective of this PA is to stimulate research into possible genetic factors in the causation of Parkinson's disease. It is hoped that the results of these investigations will help to elucidate the causes and pathogenesis of Parkinson's 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 initiated national activity for setting priority areas. This PA, Genetics of Parkinson's Disease, is related to the priority area of chronic debilitating diseases. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: Stock No. 017-001-00474-0 or Summary Report: Stock No. 017-001-00473-1) through the Superintendent of Documents, Government Printing Office, Washington, DC 20402-9325 (Telephone (202) 783-3238). ELIGIBILITY REQUIREMENTS Applications may be submitted by domestic and foreign, for-profit and non-profit, public and private organizations, such as universities, colleges, hospitals, laboratories, units of state and local governments, and eligible agencies of the federal government. Foreign institutions are not eligible for program project grants (P01) or First Independent Research Support and Transition (FIRST) (R29) awards. Racial/ethnic minority individuals, women, and persons with disabilities are encouraged to apply as principal investigators. MECHANISM OF SUPPORT The mechanisms available for support of this PA are the National Institutes of Health (NIH) research project (R01), program project (P01), and the FIRST (R29) award. Responsibility for the planning, direction and execution of the proposed research project will be solely that of the applicant. Because the nature and scope of the research proposed in response to this PA may vary, it is anticipated that the size of an award will also vary. Applications submitted in response to this announcement will compete with all investigator-initiated applications and be reviewed according to the customary peer review procedures. All applications will receive an assignment to the appropriate institute in accordance with the extant Referral Guidelines. FUNDS AVAILABLE Applications will compete for all available extramural grant funds on the basis of scientific merit as judged by peer review. RESEARCH OBJECTIVES Background Parkinson's disease (PD) is a common and disabling progressive neurodegenerative disorder characterized by tremor, rigidity, bradykinesia, and loss of postural reflexes. It affects some half million Americans. The pathology is a rather specific pattern of neuronal degeneration associated with Lewy-body formation in the substantia nigra and other regions of the brain. PD responds for a time to medication but is a progressive disorder. There is no specific biological test for the diagnosis of PD. Twin studies have shown variable results and suggest that the genetics of this disorder will prove to be complex. Despite the importance and severity of PD and despite many years of research, a cause has not been identified and there is no means of preventing the disease and no proven permanent cure. Familial parkinsonism has been recognized recently to be more frequent than was thought previously. Some physicians state that it is more prevalent in clinical practice than familial Alzheimer's disease or familial amyotrophic lateral sclerosis (ALS). The signs and symptoms in familial cases of pure Parkinson's disease do not seem to differ from sporadic cases. Familial parkinsonism is heterogeneous in onset and course, and wide variations of expression may occur within families. Most cases of PD are apparently sporadic, as with ALS and Alzheimer's disease where multiple gene loci have been found. There have been reported a growing list of small multicase PD families and a few large possibly autosomal dominant PD pedigrees. Several families in which Parkinson's disease seems to be inherited have been followed over successive generations. Sharing information on these families and subjecting the data to sophisticated computer analysis could hasten the identification of a genetic basis or predisposition in this disorder. Through linkage and allele sharing analysis of special populations of Parkinson's disease families, it may be possible to identify the gene or genes that increase the risk for the disorder. Special populations would include families with many affected members, families that are geographically restricted, those in which the origin of the disorder in that family may be traced back to a single individual, or those that have an early age of onset or unusual severity. Restricting the phenotype to be studied by eliminating from analysis those members of a family who do not have typical Parkinson's disease may enhance the opportunity to localize the gene. Some large families show apparent autosomal dominant inheritance with high penetrance. In small multicase families, the inheritance pattern is compatible with either autosomal dominance with reduced penetrance or multifactorial inheritance. The apparent paucity of parental consanguinity indicates no recessive inheritance. Anticipation and X-linked inheritance are not thought to be involved in PD. Findings which would be of considerable importance in this search would be the location of a genetic marker, determination of the probability of penetrance, determination of possible genetic heterogeneity, and evidence of multifactorial inheritance with environmental interaction. Finding genetic factors determining susceptibility to PD will enhance epidemiological studies and possibly lead to identification of susceptible groups and of significant risk factors. The areas of genetic research discussed in this section , however, are not intended to be comprehensive or exclusionary. Researchers responding to this PA are encouraged to consider novel approaches of the broadest nature in approaching the pathogenesis of this disease. 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) and supersedes and strengthens the previous policies (concerning the inclusion of women in study population, and concerning the inclusion of minorities in study populations), which have been in effect since 1990. The current policy contains some provisions that are substantially different from the 1990 policies. 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 reprinted in the NIH Guide for Grants and Contracts, Volume 23, Number 11, March 18, 1994. Investigators also may obtain copies of the policy from the program staff listed under inquiries. Program staff may also provide additional relevant information concerning the policy. APPLICATION PROCEDURES The research grant application form PHS 398 (REV. 05/95) is to be used in applying for these grants. Applications kits are available at most institutional offices of sponsored research and may be obtained from the Grants Information Office, Office of Extramural Outreach and Information Resources, National Institutes of Health, 6701 Rockledge Drive, MSC 7910, Bethesda, MD 20892-7910, telephone 301/710-0267, email: ASKNIH@odrockm1.od.nih.gov. FIRST (R29) award applications must include at least three sealed letters of reference attached to the face page of the original application. FIRST applications submitted without the required number of reference letters will be considered incomplete and will be returned without review. In addition, the PA title, ("Genetics of Parkinson's Disease" NS-96 ) should be typed on line 2 of the face page of the application form and the yes box should be marked. Submit a signed typewritten original of the application, including the checklist, and three signed photocopies, in one package to: DIVISION OF RESEARCH GRANTS NATIONAL INSTITUTES OF HEALTH 6701 ROCKLEDGE DRIVE, ROOM 1040 - MSC 7710 BETHESDA, MD 20892-7710 BETHESDA, MD 20817 (for courier or express service) REVIEW CONSIDERATIONS Applications that are complete and responsive to the PA will be evaluated for scientific and technical merit in accordance with the review criteria stated below, by an appropriate peer review group. As part of the initial merit review, all applications will receive a written critique and undergo a streamlined (triage) review process in which only those applications deemed to have the highest scientific merit will be discussed, assigned a priority score, and receive a second review by the National Advisory Council, where applicable. REVIEW CRITERIA Criteria for scientific/technical merit review of applications are the following: o Significance and originality of proposed research from a scientific or technical standpoint; o Qualifications and experience of the principal investigator and the staff in areas specifically related to the questions under investigation; o Adequacy of the conceptual and technical framework for the research, including evidence of familiarity with relevant research literature and proposed techniques; o Access to appropriate study population (s), specimens, and equipment; o Adequacy of plan to include both genders and minorities and their subgroups as appropriate for the scientific goals of the research. Plan for the recruitment and retention of subjects will also be evaluated; o Adequacy of the existing and proposed facilities and resources; o Adequacy of the data analysis plan; o Appropriateness of the proposed budget, staffing plan, and the time frame in relation to the proposed project. The initial review group will also examine the provisions for the protection of human subjects and the safety of the research environment. AWARD CRITERIA The following criteria will be considered in making a funding decision: o Scientific merit as determined during the peer review process and availability of funds. INQUIRIES Inquiries concerning this PA are encouraged. The opportunity to clarify any issues or questions from potential applicants is welcome. Inquiries regarding programmatic issues may be directed to: Eugene J. Oliver, Ph.D. Division of Demyelinating, Atrophic, and Dementing Disorders National Institute of Neurological Disorders and Stroke Federal Building, Room 806 7550 Wisconsin Avenue Bethesda, MD 20892-9150 Telephone: (301) 496-1431 FAX: (301) 402-2060 Email: eo11c@nih.gov Direct inquiries regarding fiscal matters to: Ms. Pat Driscoll Grants Management Branch National Institute of Neurological Disorders and Stroke Federal Building, Room 1004 7550 Wisconsin Avenue Bethesda, MD 20892-9190 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, 93.853 and 93.854 for Neurological Disorders and Stroke Grants. 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 PHS grants policies and Federal regulations 42 CFR 52 and 45 CFR Part 74. 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 to 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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