Genetic and Environmental Risk Factors for PSP

PSP 的遗传和环境风险因素

• 批准号: 7096316
• 负责人: Irene Litvan
• 金额: $ 62.89万
• 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/7096316
• 关键词: alpha synuclein; brain injury; clinical research; disease /disorder etiology; disease /disorder proneness /risk; environmental exposure; gene environment interaction; gene interaction; gene mutation; genetic polymorphism; genetic screening; haploidy; human subject; hypertension; interview; leucine; medical records; occupational health /safety; parkin gene /protein; pathologic process; patient oriented research; plant insecticide; progressive supranuclear palsy; telecommunications; trauma

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）：渐进性上核瘫（PSP）是一种零星的tauopathy，其原因是未知的。 H1 Tau单倍型与其病因有关。但是，它也存在于60％的正常对照中。这与晚期症状发作相结合，表明仅遗传学不会引起PSP。对环境因子假说的支持源于动物模型以及PSP之间观察到的与线粒体复合物I抑制剂（即乙蛋白酶）之间的关联，这些抑制剂是神经毒性与多巴胺能神经元的神经毒性。 PSP线粒体中的代谢受损和受影响的大脑区域的氧化损伤也支持这一假设。因此，基因和环境可以单独或通过它们的互动发挥作用。该应用将确定：1）如果PSP和HI/HI基因型之间存在关联，特定的HI子型型，α-核蛋白多态性或Parkin基因缺陷，或者是否存在基因 - 基因相互作用； 2）如果PSP职业和/或环境化学物质暴露在功能或结构上与烤面包酮/actegogenin之间存在关联； 3）如果症状发作之前的高血压或脑损伤与PSP有关。为了解散PSP的复杂病因，此病例对照多中心研究涉及500例PSP病例，500个年龄/性别匹配的主要控制和500个二级控制，用于遗传确认。由于大小，范围或结构的限制，先前的病例对照研究尚无定论。这是第一个具有匹配控制的PSP案例，具有必要的基础架构来解决我们的假设并探索基因 - 环境相互作用。结果，它将有助于解决有关PSP原因的争议，并刺激发病机理研究和预防性疗法的新途径。了解PSP的病因也可能有助于解释其他tauopathies（例如阿尔茨海默氏病）的原因。这支多学科运动专家，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非常适合揭示PSP复杂的病因。使用NINDS细胞存储库进行遗传库存也将允许与其他研究人员共享DNA样本。