Center for Gene Environment in Parkinson's Disease

帕金森病基因环境中心

• 批准号: 7914230
• 负责人: MARIE-FRANCOISE S CHESSELET
• 金额: $ 129.53万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-15 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914230
• 关键词: Center; Gene; Environment; Parkinson; Disease

The major theme of the UCLA CENTER FOR GENE ENVIRONMENT IN PARKINSON DISEASE (PD) is to identify novel mechanisms of pathogenesis for sporadic PD by understanding the primary cellular mechanisms by which agricultural pesticides that we and others have demonstrated to be risk factors for PD. produce dysfunction and death of dopamine neurons in cellular and animal models, and lead to PD in humans. Our group has begun to identify an association between exposure to specific pesticides and an increased risk for PD in an exceptionally well-characterized patient cohort in the agricultural region of California Central Valley. In parallel experiments, we have discovered that several of these pesticides affect specific cellular pathways potentially involved in PD. In particular, we have evidence that several agricultural pesticides associated with an increased risk of PD interfere with the ubiquitin-proteasome system (UPS). In addition to their effects on the proteasome, these pesticides to varying extent interfere with microtubule assembly, and/or inhibit aldehyde dehydrogenase, a key detoxification enzyme. The central hypothesis to be tested in the Center is that disruption of these particular cellular mechanisms by some agricultural pesticides is responsible for their ability to increase the risk of PD. Four integrated projects will combine human-based studies in a unique epidemiological cohort (project 4) with basic research studies in cellular (project 1), Drosophila (project 2) and rodent (project 3) models. We expect that the results of our studies will identify novel molecular pathways involved in neurodegeneration in PD, and specific therapeutic targets to stop or reverse the course of the disease. In addition, a better understanding of the potential neurotoxicity of widely used pesticides will have implications for their use in the environment to protect the health of workers and the general population, who are exposed to environmental pesticides in or near agricultural settings.

加州大学洛杉矶分校帕金森病（PD）基因环境中心的主要主题是 通过了解我们和其他人已经证明是PD危险因素的农药的主要细胞机制，确定散发性PD发病的新机制。在细胞和动物模型中产生多巴胺神经元的功能障碍和死亡，并导致人类的PD。我们的研究小组已经开始在一个特征非常明确的患者队列中确定暴露于特定农药与帕金森病风险增加之间的关联，该患者队列位于美国的农业地区。 加州中央谷。在平行实验中，我们发现这些杀虫剂中的几种影响可能参与PD的特定细胞通路。特别是，我们有证据表明，与PD风险增加相关的几种农药干扰了泛素-蛋白酶体系统（UPS）。 除了它们对蛋白酶体的影响之外，这些农药在不同程度上干扰微管组装，和/或抑制醛脱氢酶，一种关键的解毒酶。该中心将测试的核心假设是，一些农药对这些特定细胞机制的破坏是其增加PD风险的能力的原因。四个综合项目将把联合收割机在一个独特的流行病学队列中进行的以人为基础的研究（项目4）与以下方面的基础研究结合起来： 细胞（项目1）、果蝇（项目2）和啮齿动物（项目3）模型。我们希望我们的研究结果将确定参与PD神经变性的新分子途径，以及阻止或逆转疾病进程的特定治疗靶点。此外，更好地了解广泛使用的农药的潜在神经毒性将对它们在环境中的使用产生影响，以保护环境。 在农业环境中或其附近接触环境农药的工人和一般人群的健康。