Molecular Epidemiology of Parkinson's Disease

帕金森病的分子流行病学

• 批准号: 6922317
• 负责人: DEMETRIUS MICHAEL MARAGANORE
• 金额: $ 120.74万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-09-30 至 2010-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6922317
• 关键词: Parkinson' s disease; alcoholic beverage consumption; alcoholism /alcohol abuse; biomarker; caffeine; clinical research; estrogens; family genetics; gene environment interaction; genetic polymorphism; genetic susceptibility; human subject; linkage disequilibriums; mental health epidemiology; nervous system disorder epidemiology; patient oriented research; pesticide biological effect; quality of life; substance abuse related disorder; tobacco abuse

DESCRIPTION (provided by applicant): This is a competing continuation application for the grant ES10751 entitled "Molecular Epidemiology of Parkinson's Disease". Key steps in the pathogenesis of Parkinson's disease (PD) may include increased soluble alpha-synuclein and its aggregation and fibrillization. These events are attenuated by protein degradation and fibril sequestration. The linkage-derived genes alpha-synuclein (SNCA), ubiquitin carboxy-terminal hydrolase L1 (UCHL1), microtubule-associated protein tau (MAPT), and parkin (PRKN) confer PD susceptibility, possibly via their effects on this pathogenesis pathway. We postulate that functional variability in these four genes and their joint effects modify PD severity outcomes, and that age, gender, and environmental factors also contribute to susceptibility and outcomes. We propose renewal of our grant ES10751 with the following 3 specific aims: A1. To refine the association between linkage-derived susceptibility genes and PD. Human, primate, and rodent cross-species sequence conservation will be used to highlight functional domains within the SNCA, UCHL1, MAPT, and PRKN loci. Additional variants, including single nucleotide polymorphisms (SNPs), will be identified within these regions (VISTA or "vSNPs"). Linkage disequilibrium will be used to identify haplotype-tagging variants ("ht-SNPs"). Family-based and case-control association analyses will be performed in an expanded Mayo sample of 1,500 matched pairs of PD cases and unaffected siblings or unrelated population controls. A2. To study interactions of these genes, and their interactions with environmental and gender-related factors. Using data from aim 1, we will apply recursive partitioning and conditional logistic regression approaches to investigate the joint effects of SNCA, UCHL1, MAPT, and PRKN on PD. We will also determine how these genes interact with environmental risk factors including pesticides, tobacco, coffee, and alcohol. In addition, we will assess how gender and endogenous or exogenous estrogen modify these interactions in women. A3. To study genetic factors influencing PD outcomes. In an established cohort of 1,000 Mayo PD patients, we will perform longitudinal assessments and conduct survival and regression analyses to determine whether polymorphism in the SNCA, UCHL1, MAPT, and PRKN genes correlates with disease severity outcomes. In particular, we will consider death, nursing home placement, incident dementia, and Hoehn and Yahr stage. We will also consider activities of daily living, complications of therapy, and quality of life. The first two aims will refine our understanding of molecular targets for neuroprotective therapies, and the third aim will predict their efficacy. Our findings will contribute to early disease detection (biomarkers) and primary prevention strategies. They will also accelerate the development of new treatments, reduce research and development costs, and identify subgroups of patients most likely to benefit.

描述（由申请人提供）：这是一项名为“帕金森病的分子流行病学”的 ES10751 拨款的竞争性延续申请。帕金森病 (PD) 发病机制的关键步骤可能包括可溶性 α-突触核蛋白的增加及其聚集和纤维化。这些事件因蛋白质降解和原纤维隔离而减弱。连锁衍生基因 α-突触核蛋白 (SNCA)、泛素羧基末端水解酶 L1 (UCHL1)、微管相关蛋白 tau (MAPT) 和 Parkin (PRKN) 可能通过其对该发病机制的影响而赋予 PD 易感性。我们假设这四个基因的功能变异及其联合效应会改变帕金森病的严重程度，并且年龄、性别和环境因素也会影响易感性和结果。我们建议更新我们的拨款 ES10751，以实现以下 3 个具体目标：A1。完善连锁衍生的易感基因与 PD 之间的关联。人类、灵长类动物和啮齿动物跨物种序列保守性将用于突出 SNCA、UCHL1、MAPT 和 PRKN 基因座内的功能域。其他变体，包括单核苷酸多态性 (SNP)，将在这些区域内进行鉴定（VISTA 或“vSNP”）。连锁不平衡将用于识别单倍型标记变体（“ht-SNP”）。基于家庭的病例对照关联分析将在 Mayo 扩大样本中进行，样本包括 1,500 对匹配的 PD 病例和未受影响的兄弟姐妹或不相关的人群对照。 A2。研究这些基因的相互作用，以及它们与环境和性别相关因素的相互作用。使用目标 1 中的数据，我们将应用递归划分和条件逻辑回归方法来研究 SNCA、UCHL1、MAPT 和 PRKN 对 PD 的联合影响。我们还将确定这些基因如何与杀虫剂、烟草、咖啡和酒精等环境风险因素相互作用。此外，我们将评估性别和内源性或外源性雌激素如何改变女性的这些相互作用。 A3。研究影响 PD 结果的遗传因素。在已建立的 1,000 名 Mayo PD 患者队列中，我们将进行纵向评估并进行生存和回归分析，以确定 SNCA、UCHL1、MAPT 和 PRKN 基因的多态性是否与疾病严重程度结果相关。我们将特别考虑死亡、疗养院安置、痴呆事件以及 Hoehn 和 Yahr 阶段。我们还将考虑日常生活活动、治疗并发症和生活质量。前两个目标将加深我们对神经保护疗法分子靶点的理解，第三个目标将预测其疗效。我们的研究结果将有助于早期疾病检测（生物标志物）和一级预防策略。他们还将加速新疗法的开发，降低研发成本，并确定最有可能受益的患者亚组。