CATECHOL THIOETHERS IN PARKINSON'S DISEASE

描述：(摘自申请者的摘要)帕金森氏病(PD)是一种 给美国带来了严重的公共卫生问题。尽管取得了巨大的进步 对帕金森氏病的临床治疗有了一定的认识 其神经退行性变的机制尚不完整。是这样的 知识将是未来阻碍治疗的发展所必需的 或者阻止帕金森氏症的发展。的长期目标 这个项目是为了确定氧化产物的作用机制 多巴胺和相关的儿茶酚，儿茶酚硫醚，可以转化为 神经毒素导致黑质纹状体氧化损伤和 神经退行性变。本项目的具体目标是：(1)确定 硫代尿酸产生的内源性邻苯二酚硫醚的效价 多巴胺能神经通路及其可能的作用机制 整个线粒体、培养的多巴胺能神经元、脑内的神经变性 衰老对照和基因工程小鼠的区域缺乏 抗氧化防御，(2)测定硫代尿酸的活性 途径酶与脑组织中儿茶酚硫代碳酸酯的浓度 帕金森病患者脑区和脑脊液及其他黑质纹状体 神经退行性疾病和年龄匹配的对照组，以及(3)确定 环境毒物与环境毒物流行病学联系的机制 帕金森病风险增加可能会增加儿茶酚的神经毒性 硫醚。这一新信息将决定儿茶酚的含量 在硫代尿酸途径中产生的硫醚可能有助于 帕金森病进展，与衰老和环境相互作用 与帕金森氏症有关的毒物，并作为维生素 黑质纹状体变性的生物标志物。

DESCRIPTION: (adapted from applicant's abstract) Parkinson's disease (PD) is a serious public health problem for the United States. Although dramatic advances have been made in the clinical management of Parkinson's disease, understanding of the mechanisms that underlie its neurodegeneration is incomplete. Such knowledge will be necessary for future development of therapeutics that impede or halt the progression of Parkinson's disease. The long-term objectives of this project are to determine the mechanisms by which oxidation products of dopamine and related catechols, catechol thioethers, may be converted to neurotoxins that contribute to nigrostriatal oxidative damage and neurodegeneration. The Specific Aims of this projects are: (1) to determine the potency of endogenous catechol thioether produced in the mercapturic acid pathway and the mechanisms by which they may contribute to dopaminergic neurodegeneration in whole mitochondria, cultured dopaminergic neurons, brain regions of aged control and genetically engineered mice with deficiencies in anti-oxidant defenses, (2) to determine the activities of mercapturic acid pathway enzymes and the concentration of catechol mercapturates in brain regions and CSF from patients with Parkinson's disease, other nigrostriatal neurodegenerative diseases, and aged-matched controls, and (3) to determine the mechanisms by which environmental toxicants epidemiological linked with an increased risk of Parkinson's disease may augment neurotoxicity form catechol thioethers. This new information will determine the extent to which catechol thioethers produced in the mercapturic acid pathway may contribute to Parkinson's disease progression, interact with aging and environmental toxicants implicated in Parkinson's disease, and serve as intra vitam biomarkers of nigrostriatal degeneration.