Genetic and Environmental Risk Factors for PSP

PSP 的遗传和环境风险因素

• 批准号: 7457789
• 负责人: Irene Litvan
• 金额: $ 54.31万
• 依托单位: UNIVERSITY OF LOUISVILLE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-15 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7457789
• 关键词: Address; Affect; Age; Alzheimer' s Disease; Animal Model; Area; Brain; Carbon Disulfide; Carbon Monoxide; Case-Control Studies; Cells; Chemicals; Chronic; Class; Clinical; Collaborations; Complex; Coupled; DNA; Deltastab; Development; Diagnosis; Disease; Enrollment; Environment; Environmental Exposure; Environmental Risk Factor; Epidemiologist; Etiology; Exposure to; Family; First Degree Relative; Future; Gender; Gene Mutation; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Goals; Haplotypes; Herbicides; Hypertension; Injury; Intervention; Knowledge; Lead; Manganese; Metabolism; Methodology; Mitochondria; Movement Disorders; Multicenter Studies; Mutation; Neurodegenerative Disorders; Occupational; Organic solvent product; Paralysed; Parkin gene; Pathogenesis; Patients; Pattern; Personal Satisfaction; Pesticides; Play; Progressive Supranuclear Palsy; Purpose; Questionnaires; Range; Recording of previous events; Research; Research Infrastructure; Research Personnel; Resources; Risk; Risk Factors; Role; Rotenone; Sampling; Secondary Parkinson Disease; Series; Severity of illness; Site; Specialist; Structure; Suggestion; Symptoms; Tauopathies; Testing; Tetrahydroisoquinolines; Transition Elements; Traumatic Brain Injury; Variant; Work; acetogenin; alpha synuclein; base; carbamate insecticide; case control; design; dopaminergic neuron; environmental chemical exposure; gene interaction; genetic risk factor; inhibitor/antagonist; leucine-rich repeat kinase 2; multidisciplinary; neurotoxic; parkin gene/protein; programs; promoter; prophylactic; repository; size; sodium arsenite; stem; synuclein; tau Proteins; tau-1

DESCRIPTION (provided by applicant): Progressive supranuclear palsy (PSP) is a sporadic tauopathy with unknown cause. The H1 tau haplotype is implicated in its etiology; however, it is also present in 60% of normal controls. This, coupled with late symptom onset, indicates that genetics alone does not cause PSP. Support for the environmental factor hypothesis stems from animal models and the observed association between PSP and exposure to mitochondrial complex I inhibitors (i.e., acetogenins), which are neurotoxic to dopaminergic neurons. Impaired metabolism in PSP mitochondria and oxidative injury in affected brain areas also support this hypothesis. Hence, genes and environment may both play a role either alone or through their interactions. This application will determine: 1) if there is an association between PSP and the HI/HI genotype, specific HI sub-haplotypes, alpha-synuclein polymorphisms or parkin gene deficits, or if there are gene-gene interactions; 2) if there is an association between PSP occupational and/or environmental chemical exposures functionally or structurally similar to rotenone/acetogenins; and 3) if hypertension or traumatic brain injury prior to symptom-onset is associated with PSP. To disentangle the complex etiology of PSP, this case-control multicenter study involves 500 PSP cases, 500 age/gender matched primary controls, and 500 secondary controls for genetic confirmation. Previous case-control studies have been inconclusive because of limitations in size, scope, or structure. This is the first adequately powered series of PSP cases with matched controls that has the necessary infrastructure to address our hypotheses and explore gene-environmental interactions. As a result, it will help resolve controversies concerning the cause(s) of PSP and will stimulate new avenues of pathogenesis research and prophylactic therapies. Understanding the etiology of PSP may also help explain the causes of other tauopathies such as Alzheimer's disease. This multidisciplinary team of movement disorder specialists, epidemiologists, geneticists, biostatisticians, industrial hygienist and toxicologist is well suited to unravel the complex etiology of PSP. The use of the NINDS cell repository for genetic banking will also allow DNA sample sharing with other investigators.

描述（由申请人提供）：进行性核上性麻痹（PSP）是一种原因不明的散发性tau蛋白病。H1 tau单倍型与其病因有关;然而，它也存在于60%的正常对照中。这一点，加上后期症状发作，表明遗传本身并不导致PSP。对环境因素假说的支持源于动物模型和观察到的PSP与暴露于线粒体复合物I抑制剂之间的关联（即，acetogenins），其对多巴胺能神经元具有神经毒性。PSP线粒体的代谢受损和受影响脑区的氧化损伤也支持这一假设。因此，基因和环境都可以单独或通过它们的相互作用发挥作用。此应用程序将确定：1）PSP与HI/HI基因型、特定HI亚单倍型、α-突触核蛋白多态性或parkin基因缺陷之间是否存在关联，或者是否存在基因-基因相互作用; 2）PSP职业和/或环境化学品暴露之间是否存在功能或结构上类似于鱼藤酮/乙酮的关联;（3）PSP发病前是否伴有高血压或创伤性脑损伤。为了解开PSP的复杂病因，这项病例对照多中心研究涉及500例PSP病例，500例年龄/性别匹配的初级对照，以及500例用于遗传确认的次级对照。以前的病例对照研究由于规模、范围或结构的限制而没有结论。这是第一个有足够动力的PSP病例系列，具有匹配的对照，具有必要的基础设施来解决我们的假设并探索基因-环境相互作用。因此，它将有助于解决有关PSP病因的争议，并将刺激发病机制研究和预防治疗的新途径。了解PSP的病因也可能有助于解释其他tau蛋白病如阿尔茨海默病的原因。这个由运动障碍专家、流行病学家、遗传学家、生物统计学家、工业药物学家和毒理学家组成的多学科团队非常适合解开PSP的复杂病因。使用NINDS细胞库进行基因库也将允许与其他研究人员共享DNA样本。