Toxicant-induced neurotoxicity mediated by glia-neuron and gene-environment interactions in Parkinson's disease

我们实验室的长期目标是研究 帕金森病的环境毒物、基因突变和基因-环境相互作用 疾病（PD），最终目标是为这种大脑开发疾病修饰疗法 disorder.总的来说，我们的研究项目解决了以下基本问题：1）基因- 环境相互作用：与PD相关的突变是否会使多巴胺神经元 易受环境毒物的影响2)神经胶质-神经元相互作用：神经胶质细胞如何发挥作用 帕金森病患者多巴胺神经元的脆弱性3)过度的线粒体分裂 在遗传和毒物诱导的PD模型中得到证实。线粒体分裂和 融合是否可作为PD治疗的靶点？这些研究课题目前由家长资助 授予（R35 ES 030523）。这一补充要求支持暑期学生。 在父母资助中，我们假设阻断Drp 1可以减弱自噬损伤， 锰（Mn）引起的。从那时起，我们已经产生了体外和体内数据， 支持这一假设。然而，到目前为止，重点一直是神经元。假设Mn也 影响星形胶质细胞和小胶质细胞，评估Mn和Drp 1在这些细胞中的作用至关重要。 神经胶质细胞在这个暑期项目中，学生将使用来自 Drp 1-KO小鼠和WT研究Mn对这些细胞类型中自噬的影响，以及Mn是否 Drp 1-KO会起到保护作用。这项研究是高度相关和补充的父母 项目成功完成这项研究将提供初步数据，以推进家长 项目使用体内模型来进一步研究这些体外数据。

The long term goal of our laboratory is to study the pathogenic mechanisms induced by environmental toxicants, genetic mutations and gene-environment interactions in Parkinson’s disease (PD) with the ultimate goal of developing disease-modifying therapeutics for this brain disorder. Overall, our research projects address the following fundamental questions: 1) Gene- environment interactions: Do mutations linked to PD render dopamine neurons more susceptible to environmental toxicants? 2) Glia-neuron interactions: How do glial cells contribute to the vulnerability of dopamine neurons in PD? 3) Excessive mitochondrial fission has been demonstrated in genetic and toxicant-induced models of PD. Can mitochondrial fission and fusion be targeted for PD treatment? These research topics are currently funded by the parent grant (R35ES030523). This supplement is requested to support a summer student. In the parent grant, we hypothesized that blocking Drp1 would attenuate autophagy impairment induced by manganese (Mn). Since then, we have generated both in vitro and in vivo data to support this hypothesis. However, so far, the focus has been on neurons. Given that Mn also affects astrocytes and microglia, it is critical to also assess the effects of Mn and Drp1 in these glial cells. For this summer project, the student will use primary astrocytes and microglia from Drp1-KO mice and WT to study the effects of Mn on autophagy in these cell types and whether Drp1-KO would be protective. This study is highly relevant and complementary to the parent project. Successful completion of this study will provide preliminary data to advance the parent project to using in vivo models to further investigate these in vitro data.