Center for Gene-Environment Studies in Parkinson Disease

加州大学洛杉矶分校帕金森病基因环境研究中心将架起桥梁 美国国立卫生研究院和退伍军人事务部资助的帕金森氏病(PD)三大奖项和一项由NIH赞助的 亨廷顿氏病。提出的UCLA-CGEP的中心假设是基因和环境 毒素通过杀虫剂之间的相互作用增加易感个体患帕金森病的风险 以及调节多巴胺动态平衡的机制。我们假设，这种互动中的关键因素是 氧化应激和由此引起的蛋白酶体功能的改变。项目I“环境毒素和基因 影响果蝇和人类中的多巴胺“将检测多巴胺的个体间变异性 囊泡转运蛋白(VMAT)在两个人群中因启动子变异而表达 报告基因分析。将对这些人群进行VMAT2功能变异和关联的基因分型 在家长资助中收集的基因-环境相互作用和农药暴露的分析将是 指挥。此外，还将利用果蝇遗传学来确定VMAT的表达如何影响 并确定调节VMAT功能的基因，然后将在 人类人口与帕金森病风险增加的相关性。项目二“农药之间的相互作用 而小鼠体内多巴胺稳态的遗传变化将检验杀虫剂和遗传基因 组合的变异增加了多巴胺能神经元的脆弱性，而其中一个 涉及的机制是氧化应激。基因工程小鼠的表达降低 VMAT或细胞质多巴胺转运体，以及α-突触核蛋白和α-突触核蛋白表达改变的小鼠 Parkin是两种已知的导致家族性帕金森病的蛋白质，将被检测。行为和数量解剖学将是 用来评估杀虫剂对这些基因改变小鼠的多巴胺能神经元的影响。组织学， 基因表达谱，体内神经化学和切片电生理学将被用来检测 氧化应激在这种相互作用中的作用。项目三，“农药和蛋白酶体功能障碍：遗传 细胞模型中的易感性“将检验蛋白酶体功能障碍是 环境和遗传侮辱相结合的有害影响。神经元原代培养细胞系 来自转基因小鼠的基因，以及人类的淋巴母细胞。

The Center for Gene-Environment studies in Parkinson disease at UCLA (UCLA-CGEP) will bridge three major NIH and VA-supported awards in Parkinson's disease (PD) and one NIH-sponsored study of Huntington's disease. The central hypothesis of the proposed UCLA-CGEP is that gene and environmental toxins combine to increase the risk for PD in susceptible individuals through an interplay between pesticides and mechanisms regulating dopamine homeostasis. We postulate that critical factors in this interaction are oxidative stress and resulting alterations in proteasomal function. Project I "Environmental toxins and genes that influence dopamine in Drosophila and humans" will examine interindividual variability of dopamine vesicular transporter (VMAT) expression due to promoter variants in two human populations in parallel with a reporter gene assay. These populations will be genotyped for functional VMAT2 variants and association analyses of gene-environment interactions and pesticide exposures collected in the parent grant will be conducted. In addition, Drosophila genetics will be used to determine how the expression of VMAT affects dopamine-mediated toxicity and identify genes that modulate VMAT function, which will then be examined in the human population for their relevance to increased risk of PD. Project II "Interaction between pesticides and genetic alterations in dopamine homeostasis in mice" will test the hypothesis that pesticides and genetic variations in combination increase the vulnerability of dopaminergic neurons, and that one of the mechanisms involved is oxidative stress. Genetically engineered mice with a reduction in expression of VMAT or the cytoplasmic dopamine transporters, and mice with altered expression of alpha-synuclein and parkin, two proteins known to cause familial PD, will be examined. Behavior and quantitative anatomy will be used to assess the effect of pesticides on dopaminergic neurons in these genetically altered mice. Histology, gene expression profiling, in vivo neurochemistry and slice electrophysiology will be used to examine the role of oxidative stress in this interaction. Project III, "Pesticides and Proteasomal Dysfunction: genetic susceptibility in cellular models" will test the hypothesis that proteasomal dysfunction is central to the deleterious effects of the combined environmental and genetic insults. Cell lines, primary neuronal cultures from genetically altered mice, and human lymphoblasts will be examined.