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（UCLA-CGEP）将在 三项NIH和VA支持的帕金森病（PD）研究和一项NIH赞助的亨廷顿病研究。拟议的UCLA-CGEP的中心假设是基因和环境毒素联合收割机通过杀虫剂和调节多巴胺稳态的机制之间的相互作用增加易感个体的PD风险。我们假设，在这种相互作用的关键因素是氧化应激和蛋白酶体功能的改变。项目I“影响果蝇和人类多巴胺的环境毒素和基因”将研究由于两个人群中的启动子变体而导致的多巴胺囊泡转运蛋白（VMAT）表达的个体间差异，同时进行报告基因测定。将对这些群体进行功能性VMAT 2变体和相关性的基因分型。 研究人员会分析基因与环境的相互作用，以及家长补助金中收集到的农药暴露数据。此外，果蝇遗传学将用于确定VMAT的表达如何影响多巴胺介导的毒性，并确定调节VMAT功能的基因，然后在人群中检查其与PD风险增加的相关性。项目II“杀虫剂与小鼠多巴胺稳态遗传改变之间的相互作用”将检验杀虫剂和遗传变异相结合会增加多巴胺能神经元脆弱性的假设，其中一个机制是氧化应激。将检查VMAT或细胞质多巴胺转运蛋白表达减少的基因工程小鼠，以及α-突触核蛋白和parkin（已知引起家族性PD的两种蛋白质）表达改变的小鼠。行为和定量解剖学将是 用于评估杀虫剂对这些基因改变小鼠多巴胺能神经元的影响。组织学，基因表达谱，在体内神经化学和切片电生理学将被用来研究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：细胞模型中的遗传易感性”将测试蛋白酶体功能障碍是环境和遗传损伤相结合的有害影响的核心的假设。将检查细胞系、遗传改变小鼠的原代神经元培养物和人成淋巴细胞。

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.