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沙门氏菌引起的致病机制 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)，最终目标是为这个大脑开发疾病修正疗法 无序。总体而言，我们的研究项目涉及以下基本问题：1)基因- 环境相互作用：与帕金森病相关的突变是否会使多巴胺神经元更容易受到影响 环境毒物？2)胶质细胞-神经元相互作用：神经胶质细胞如何参与 PD中多巴胺神经元的脆弱性？3)线粒体过度分裂 在遗传和毒物诱导的帕金森病模型中得到证实。线粒体的分裂和融合 是帕金森病治疗的靶子吗？这些研究项目一直得到NIEHS的支持 2006年。这份R35提案将建立在实力、专业知识、实验模型和其他 NIEHS资助我们实验室的项目所产生的资源，将我们的工作带到 下一个变革性的层次。R35提案的主要目标是证明 锰等神经毒物单独或联合作用所致的神经毒性 其他与帕金森病有关的因素(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(Drp1)的功能，通常被称为线粒体分裂 蛋白。然而，我们最近的发现使我们发现了令人意想不到的和令人兴奋的drp1机制 通过自噬。结合我们最近发现的神经毒物，如锰和 百草枯在低浓度和亚致死浓度下损害自噬，我们的愿景是Drp1在 在致病机制中起中心作用，该蛋白可作为帕金森病治疗的靶点。超过了 未来八年，这款R35将赋予我们灵活性和权力，全面调查 Drp1参与神经胶质细胞-神经元相互作用、基因-环境介导的神经毒性 与帕金森病有关的相互作用和胃细菌。这项建议利用了 来自一支经验丰富的调查人员团队的跨学科方法 记录、广泛的化学和遗传工具、高标准技术和 分子靶标操作的创新实验模型及其功能研究 细胞水平、回路水平和整体动物水平。该项目的完成将在以下方面提供范式转变 我们对Drp1如何通过广泛的毒性侮辱来调节神经毒性的理解。

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.