THE HEREDITARY ATAXIAS INCLUDING MACHADO-JOSEPH DISEASE NIH GUIDE, Volume 21, Number 9, March 6, 1992 PA: PA-92-48 P.T. 34 Keywords: Genetics Pathophysiology Molecular Genetics Diagnosis, Medical Epidemiology National Institute of Neurological Disorders and Stroke PURPOSE The Convulsive, Developmental, and Neuromuscular Disorders Program of the National Institute of Neurological Disorders and Stroke (NINDS) encourages the submission of applications for research grants related to the hereditary ataxias including Machado-Joseph Disease (MJD). The NINDS invites grant applications to support research on all aspects of this heterogeneous group of inherited degenerative disorders including pathophysiology, epidemiology, molecular genetics, diagnosis, and treatment. HEALTHY PEOPLE 2000 The Public Health Service (PHS) is committed to achieving the health promotion and disease prevention goals of "Healthy People 2000," a PHS-led national activity for setting priorities. This program announcement, The Hereditary Ataxias Including Machado-Joseph Disease, is related to the priority areas of physical activity and fitness, and chronic disabling conditions. Potential applicants may obtain a copy of "Healthy People 2000" (Full Report: No. 017-001-474-0, 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 foreign and domestic, 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. Applications from minority individuals and women are encouraged. However foreign institutions are not eligible for the First Independent Research Support and Transition (FIRST) Award (R29). MECHANISMS OF SUPPORT Applicants may use the Research Project Grant (RO1), Research Program Project (PO1), Research Center Grant (P50), and First Independent Research Support and Transition Award (R29). Prospective applicants are encouraged to communicate with the NINDS program contact listed at the end of the announcement regarding the appropriate funding mechanism. RESEARCH OBJECTIVES The hereditary ataxias, in general, encompass a variety of degenerative disorders, interchangeably referred to as spinocerebellar degenerations, that are difficult to classify due to limited knowledge of etiologic factors, variability of clinical manifestations, and limited correlation between clinical signs and postmortem changes. Onset of system degenerations may span a lifetime but often begin in the first to second decade of life. In the past, the hereditary ataxias have been categorized into predominantly spinal, spinocerebellar, and pure cerebellar forms based on a "typical" clinical picture and age of onset of signs and symptoms. Familial inheritance has been clearly shown in many of these disorders, and families may exhibit x-linked recessive, autosomal dominant or recessive patterns. The predominant presentation is the development of a chronic, progressive ataxia with variable signs and symptoms referable to the cerebellum and its afferent and efferent pathways, posterior columns, pyramidal tracts, basal ganglia, brainstem nuclei, other brain regions and peripheral nerve. In addition, there may be visual impairment (optic atrophy, pigmentary retinal degeneration), hearing dysfunction (sensory neural hearing loss), dermatological manifestations, hypogonadism, dementia, and, in some disorders, definable biochemical or genetic abnormalities. Though the clinical picture may be consistent within a family, there may be gradations of presentation that result in overlap and somewhat arbitrary distinctions, between disease entities. Examples of diseases addressed in this announcement include MJD, hereditary spinocerebellar ataxias (Friedreich's Syndrome), hereditary cerebellar ataxias, ataxia-telangiectasia, hereditary spastic paraplegia, Roussy-Levy and Marinesco-Sjogren syndrome, abetalipoproteinemia (Bassen-Kornzweig syndrome), Refsum's disease and dyssynergia cerebellaris myoclonica (Ramsay Hunt syndrome). One representative example of the hereditary ataxias, MJD, is an autosomal dominant, hereditary, progressive motor system disease initially identified among families of Portuguese-Azorean descent but now identified worldwide in many ethnic groups. Three main syndromes have been described based on heterogeneity of clinical expression felt to be phenotypic variabilities of a single gene mutation. The progressive neurological deficits result in death from debilitation within 10 to 30 years of onset. To date, there is no genetic or biochemical marker. There is no effective treatment or cure. Prevention depends on limited genetic counseling of identified families. In June 1991 an NINDS-sponsored international workshop on Research Initiatives on Machado-Joseph Disease explored issues on the description of the clinical spectrum and epidemiology, neuropathology and neurochemistry, molecular genetics, and improving diagnosis and treatment. Research needs and priorities include more precise diagnosis, elucidation of the pathophysiology, molecular genetics, and treatment of this, and similar ataxic disorders. The goals of this announcement are to stimulate research in both basic science and clinical aspects related the hereditary ataxias including MJD. The scope of this program encompasses both animal and human studies that would utilize a variety of experimental approaches and methods. A major emphasis is to expand research of the underlying mechanisms of early brain degeneration inherent to each of the hereditary ataxias. Multidisciplinary and collaborative studies are encouraged. Examples of areas of potential research include, but are not limited to, the following: o Standardized definitions and diagnoses: research criteria and classifications. o Longitudinal studies that describe the natural history of disease and that provide complete descriptions of clinical signs and symptoms of disease within families. o Neuroepidemiological studies of at-risk populations. o Experimental animal models with cerebellar system degenerations that have features consistent with neuropathological changes of the disorder. o Collaborative neuropathological studies on affected and at-risk populations utilizing a variety of techniques that better identify the first cells to be affected, the progression of the disease, and the type of dysfunction that occurs in those cells prior to death. o Evaluate possible therapeutic interventions to retard the progression of disease. o Neurochemical studies to define pathophysiology and to enable premorbid diagnosis or risk determination. o Studies utilizing neurodiagnostic and neuroimaging modalities. o Collaborative efforts on genetic research with an interchange of families, probes, and results towards identifying the defective gene(s) and gene products. STUDY POPULATIONS SPECIAL INSTRUCTIONS TO APPLICANTS REGARDING IMPLEMENTATION OF NIH POLICIES CONCERNING INCLUSION OF WOMEN AND MINORITIES IN CLINICAL RESEARCH STUDY POPULATIONS NIH and ADAMHA policy is that applicants for NIH/ADAMHA clinical research grants and cooperative agreements will be required to include minorities and women in study populations so that research findings can be of benefit to all persons at risk of the disease, disorder or condition under study; special emphasis must be placed on the need for inclusion of minorities and women in studies of diseases, disorders and conditions which disproportionately affect them. This policy is intended to apply to males and females of all ages. If women or minorities are excluded or inadequately represented in clinical research, particularly in proposed population-based studies, a clear compelling rationale must be provided. The composition of the proposed study population must be described in terms of gender and racial/ethnic group. In addition, gender and racial/ethnic issues should be addressed in developing a research design and sample size appropriate for the scientific objectives of the study. This information must be included in the form PHS 398 in Section 2, A-D of the research plan AND summarized in Section 2, E, Human Subjects. Applicants/offerors are urged to assess carefully the feasibility of including the broadest possible representation of minority groups. However, NIH recognizes that it may not be feasible or appropriate in all research projects to include representation of the full array of United States racial/ethnic minority populations (i.e., Native Americans (including American Indians or Alaskan Natives), Asian/Pacific Islanders, Blacks, Hispanics). The rationale for studies on single minority population groups must be provided. For the purpose of this policy, clinical research is defined as human biomedical and behavioral studies of etiology, epidemiology, prevention (and preventive strategies), diagnosis, or treatment of diseases, disorders or conditions, including but not limited to clinical trials. The usual NIH policies concerning research on human subjects also apply. Basic research or clinical studies in which human tissues cannot be identified or linked to individuals are excluded. However, every effort should be made to include human tissues from women and racial/ethnic minorities when it is important to apply the results of the study broadly, and this should be addressed by applicants. For foreign awards, the policy on inclusion of women applies fully; since the definition of minority differs in other countries, the applicant must discuss the relevance of research involving foreign population groups to the United States' populations, including minorities. If the required information is not contained within the application, the review will be deferred until the information is provided. Peer reviewers will address specifically whether the research plan in the application conforms to these policies. If the representation of women or minorities in a study design is inadequate to answer the scientific question(s) addressed and the justification for the selected study population is inadequate, it will be considered a scientific weakness or deficiency in the study design and will be reflected in assigning the priority score to the application. All applications for clinical research submitted to NIH are required to address these policies. NIH funding components will not award grants or cooperative agreements that do not comply with these policies. APPLICATION PROCEDURES Applications are to be submitted on the grant application form PHS 398 (rev. 9/91) according to instructions contained in the application kit. Application kits are available from most institutional business offices and may be obtained from the Office of Grants Inquiries, Division of Research Grants, Westwood Building, Room 449, National Institutes of Health, Bethesda, MD 20892, telephone 301-496-7441. Check "yes" in item two on the face sheet of the application and type "The Hereditary Ataxias Including Machado-Joseph, PA-92-48." Applicants for the P01 or P50 must use the application format as described in the NINDS pamphlet, "Application Guidelines: Program Project and Clinical Research Center Grants," that may be obtained from the contacts listed under INQUIRIES. Deadlines for the receipt of applications are February 1, June 1, and October 1. The completed original application and five legible copies must be sent or delivered to: Division of Research Grants National Institutes of Health Westwood Building, Room 240 Bethesda, MD 20892** REVIEW PROCEDURES Applications will be assigned on the basis of established Public Health Service referral guidelines. Applications will be judged on scientific merit in accordance with NIH policy and procedures involving peer review. An initial review will be made by an appropriate study section of the Division of Research Grants for research grants and FIRST awards, and by an appropriate Institute or Center committee for program project and center applications. A second level of review will be made by an appropriate advisory council. AWARD CRITERIA Applications will compete for available funds with all other approved applications. The following will be used in making funding decisions: o Quality of the proposed project as determined by peer review o Availability of funds o Program balance among research areas of the announcement INQUIRIES For further information regarding this announcement, potential applicants may write or call: Giovanna M. Spinella, M.D. Developmental Neurology Branch Division of Developmental, Convulsive, and Neuromuscular Disorders National Institute of Neurological Disorders and Stroke Federal Building, Room 820 Bethesda, MD 20892 Telephone: (301 496-5821 For fiscal and administrative inquires regarding this announcement, potential applicants may write or call: Gary P. Fleming, J.D Grants Management Branch National Institute of Neurological Disorders and Stroke Federal Building, Room 1004 Bethesda, MD 20892 Telephone: (301) 496-9231 AUTHORITY AND REGULATIONS This program is described in the Catalog of Federal Domestic Assistance No. 93.853, Clinical Research Related Neurological Disorders and 93.854, Biological Basis Research in the Neurosciences. Awards are made under authorization of the Public Health Service Act, Title IV, Part A (Public Law 78-410, as amended by Public Law 99-150, 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. .
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