Genetic and Environmental Risk Factors for PSP

PSP 的遗传和环境风险因素

基本信息

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
项目类别：
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&apos 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

项目摘要

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）是一种病因不明的散发性 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。再加上症状出现较晚，表明遗传因素本身并不会导致 PSP。对环境因素假说的支持源于动物模型以及观察到的 PSP 与暴露于线粒体复合物 I 抑制剂（即乙酰丙酮素）之间的关联，线粒体复合物 I 抑制剂对多巴胺能神经元具有神经毒性。 PSP 线粒体代谢受损和受影响大脑区域的氧化损伤也支持这一假设。因此，基因和环境可能单独或通过相互作用发挥作用。该应用程序将确定：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，或者是否存在基因间相互作用； 2) PSP职业和/或环境化学物质暴露之间是否存在功能或结构上与鱼藤酮/醋精苷类似的关联； 3) 症状出现前的高血压或创伤性脑损伤是否与 PSP 相关。为了阐明 PSP 的复杂病因，这项病例对照多中心研究涉及 500 个 PSP 病例、500 个年龄/性别匹配的主要对照和 500 个用于基因确认的二级对照。由于规模、范围或结构的限制，先前的病例对照研究尚未得出结论。这是第一个具有足够动力的 PSP 案例系列，具有匹配的对照，具有解决我们的假设和探索基因-环境相互作用所需的基础设施。因此，它将有助于解决有关 PSP 病因的争议，并将激发发病机制研究和预防性治疗的新途径。了解 PSP 的病因也可能有助于解释其他 tau蛋白病（例如阿尔茨海默病）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、工业卫生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 细胞存储库进行基因库还可以与其他研究人员共享 DNA 样本。