Center for Gene Environment in Parkinson's Disease

帕金森病基因环境中心

• 批准号: 8307670
• 负责人: MARIE-FRANCOISE S CHESSELET
• 金额: $ 8.62万
• 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/8307670
• 关键词: Affect; Agriculture; Aldehydes; Animal Model; Basic Science; California; Cell Death; Cell model; Cessation of life; Collaborations; Disease; Drosophila genus; Drug Metabolic Detoxication; Environment; Enzymes; Epidemiology; Exposure to; Functional disorder; General Population; Genes; Genetic; Health; Human; Lead; Microtubules; Modeling; Molecular; Nerve Degeneration; Neurons; Parkinson Disease; Pathogenesis; Pathway interactions; Patients; Pesticides; Risk; Risk Factors; Rodent; System; Testing; Ubiquitin; aldehyde dehydrogenases; base; cohort; disorder risk; dopaminergic neuron; environmental agent; multicatalytic endopeptidase complex; neurotoxicity; novel; programs; research study; therapeutic target

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的农业农药是帕金森病危险因素的主要细胞机制，确定散发性帕金森病的新发病机制。在细胞和动物模型中导致多巴胺神经元功能障碍和死亡，并导致人类帕金森病。我们的小组已经开始在农业地区帕金森病患者队列中发现暴露于特定杀虫剂和帕金森病风险增加之间的关联。 加州中央山谷。在平行实验中，我们发现其中几种杀虫剂影响可能与帕金森病有关的特定细胞通路。特别是，我们有证据表明，几种与帕金森病风险增加相关的农业杀虫剂干扰了泛素-蛋白酶体系统(UPS)。 除了对蛋白酶体的影响外，这些农药还不同程度地干扰微管组装，和/或抑制关键的解毒酶乙醛脱氢酶。该中心要检验的中心假设是，一些农业杀虫剂破坏了这些特殊的细胞机制，导致它们有能力增加帕金森病的风险。四个综合项目将在一个独特的流行病学队列中结合以人为基础的研究(项目4)和#年的基础研究。 细胞(方案1)、果蝇(方案2)和啮齿动物(方案3)模型。我们期望我们的研究结果将确定参与帕金森病神经退行性变的新的分子途径，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杀虫剂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 在农业环境中或附近接触环境杀虫剂的工人和普通民众的健康。