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(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互动症。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，再加上症状出现较晚，表明遗传因素本身并不能引起PSP。环境因素假说的支持来自动物模型和观察到的PSP与暴露于线粒体复合体I抑制剂(即乙酰原素)之间的关联，后者对多巴胺能神经元具有神经毒性。PSP线粒体代谢受损和大脑受影响区域的氧化损伤也支持这一假说。因此，基因和环境都可能单独或通过它们的相互作用发挥作用。这项应用将确定：1)PSP与HI/HI基因型、特定的HI亚型、α-突触核蛋白多态或parkin基因缺陷是否存在关联，或者是否存在基因-基因相互作用；2)PSP职业和/或环境化学品暴露在功能或结构上类似于鱼藤酮/乙酸根素是否存在关联；以及3)症状出现前的高血压或创伤性脑损伤是否与PSP有关。为了弄清PSP复杂的病因，这项病例对照多中心研究包括500例PSP病例、500名年龄/性别匹配的一级对照和500名次级对照以进行基因确认。由于规模、范围或结构的限制，以前的病例对照研究一直没有定论。这是第一个动力充足的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和探索基因与环境的相互作用。因此，这将有助于解决关于PSP病因(S)的争议，并将为PSP的发病机制研究和预防治疗开辟新的途径。了解PSP的病因学也有助于解释其他神经官能症的原因，如阿尔茨海默病。这个由运动障碍专家、流行病学家、遗传学家、生物统计学家、工业卫生学家和毒物学家组成的多学科团队非常适合解开PSP的复杂病因。将NINDS细胞库用于基因库也将允许与其他研究人员共享DNA样本。