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)三项主要奖项和一项由NIH赞助的亨廷顿病研究。UCLA-CGEP建议的中心假设是，通过杀虫剂和调节多巴胺稳态的机制之间的相互作用，基因和环境毒素结合在一起增加了易感个体患帕金森病的风险。我们推测，这种相互作用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“环境毒素和影响果蝇和人类多巴胺的基因”将在报告基因分析的同时，检测由于启动子变异导致的两个人类群体中多巴胺囊泡转运体(VMAT)表达的个体间变异性。将对这些人群进行VMAT2功能变异和关联的基因分型 将对家长资助中收集的基因-环境相互作用和农药暴露情况进行分析。此外，还将利用果蝇遗传学来确定VMAT的表达如何影响多巴胺介导的毒性，并识别调节VMAT功能的基因，然后在人类群体中检查它们与帕金森病风险增加的相关性。项目II“杀虫剂与小鼠体内多巴胺稳态的遗传变化之间的相互作用”将检验这样一种假设，即杀虫剂和遗传变异结合在一起会增加多巴胺能神经元的脆弱性，其中一个涉及的机制是氧化应激。VMAT或细胞质多巴胺转运蛋白表达减少的基因工程小鼠，以及阿尔法-突触核蛋白和parkin表达改变的小鼠，这两种已知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联合侮辱的有害影响的中心这一假说。将检测细胞系、来自转基因小鼠的原代神经元培养物和人类淋巴母细胞。

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.