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

项目摘要 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相关的突变是否使多巴胺神经元更易受影响？ 对环境有毒物质的反应吗2)神经胶质细胞-神经元相互作用：神经胶质细胞如何促进神经元间的相互作用？ 帕金森病中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。线粒体的分裂和融合 作为PD治疗的目标？这些研究项目得到了NIEHS的支持， 2006.这个R35提案将建立在实力，专业知识，实验模型和其他 从我们实验室的NIEHS资助项目中产生的资源， 下一个转型阶段。本R35提案的主要目标是证明， 由神经毒物如锰（Mn）单独或与 与PD相关的其他因素（α-突触核蛋白和胃细菌）可以通过减少 动力蛋白相关蛋白-1（Drp 1）的功能，通常称为线粒体分裂 蛋白然而，我们最近的研究结果使我们对Drp 1的机制有了意想不到的和令人兴奋的发现 通过自噬。结合我们最近的发现，神经毒物，如锰和 百草枯在低浓度和亚致死浓度下损害自噬，我们的观点是Drp 1在体内起着重要的作用。 在致病机制中起重要作用，该蛋白可作为PD治疗的靶点。来 在接下来的八年里，R35将为我们提供灵活性和力量，以充分调查广泛的 Drp 1参与胶质细胞-神经元相互作用介导的神经毒性，基因-环境 相互作用和与PD有关的胃细菌。该提案利用了 一个由有成就的调查人员组成的团队采用跨学科方法， 跟踪记录，广泛的化学和遗传工具，高标准的技术和 分子靶点操作与功能研究的创新实验模型. 细胞、电路和整个动物水平。该项目的完成将提供以下方面的范式转变： 我们对Drp 1如何通过广泛的毒性损伤介导神经毒性的理解。

Project Summary 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 projects have been supported by NIEHS since 2006. This R35 proposal will be built upon the strength, expertise, experimental models and other resources generated from the NIEHS funded projects in our laboratory to take our work to the next transformative level. The primary goal of this R35 proposal is to demonstrate that neurotoxicity induced by neurotoxicants such as manganese (Mn) alone or in combination with other factors (α-synuclein and gastric bacteria) linked to PD can be mitigated by reducing the function of dynamin related protein-1 (Drp1), which is typically known as a mitochondrial fission protein. However, our recent findings have led us to unexpected and exciting mechanism of Drp1 through autophagy. Combined with our recent discoveries that neurotoxicants such as Mn and paraquat impair autophagy at a low and sub-lethal concentration, our vision is that Drp1 plays a central role in pathogenic mechanism and this protein can be targeted for PD therapy. Over the next eight years, this R35 will give us the flexibility and power to fully investigate the extensive involvement of Drp1 in neurotoxicity mediated by glia-neuron interactions, gene-environment interactions and gastric bacteria that have been linked to PD. This proposal utilizes a transdisciplinary approach from a team of accomplished investigators with relevant established track-records, a wide range of chemical and genetic tools, high standard techniques and innovative experimental models for molecular target manipulations with functional studies at cellular, circuit and whole animal levels. Completion of this project will provide paradigm shifts in our understanding of how Drp1 mediates neurotoxicity through a wide range of toxic insults.