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

帕金森病中神经胶质-神经元和基因-环境相互作用介导的毒物诱导的神经毒性

• 批准号: 10397027
• 负责人: KIM TIEU
• 金额: $ 83.32万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10397027
• 关键词: Address; Animals; Autophagocytosis; Bacteria; Brain Diseases; DNA Sequence Alteration; Disease; Dynamin; Environmental Risk Factor; Experimental Models; Funding; Genetic; Goals; Grant; Impairment; Laboratories; Link; Manganese; Mediating; Mitochondria; Modeling; Molecular Target; Mutation; National Institute of Environmental Health Sciences; Neuroglia; Neurons; Neurotoxins; Paraquat; Parkinson Disease; Pathogenicity; Persons; Play; Proteins; Records; Research Personnel; Research Project Grants; Resources; Role; Stomach; Techniques; Therapeutic; Toxic Environmental Substances; United States; Vision; Work; alpha synuclein; chemical genetics; disease diagnosis; dopaminergic neuron; flexibility; gene environment interaction; high standard; innovation; neurotoxicity; new therapeutic target; tool; toxicant

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.

项目概要 我们实验室的长期目标是研究致病机制 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），最终目标是开发针对该大脑的疾病缓解疗法 总体而言，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更容易受到影响 2）神经胶质细胞与神经元的相互作用：神经胶质细胞如何促进 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证实了线粒体分裂和融合。 这些研究项目从那时起就得到了 NIEHS 的支持。 2006 年。该 R35 提案将建立在实力、专业知识、实验模型和其他基础上 我们实验室 NIEHS 资助的项目产生的资源将我们的工作带到了 该 R35 提案的主要目标是证明这一点。 由神经毒物如锰 (Mn) 单独或与锰 (Mn) 组合引起的神经毒性 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 动力相关蛋白 1 (Drp1) 的功能，通常称为线粒体裂变 然而，我们最近的发现让我们发现了 Drp1 意想不到的、令人兴奋的机制。 结合我们最近的发现，神经毒物如Mn和 百草枯在低浓度和亚致死浓度下会损害自噬，我们的愿景是 Drp1 发挥作用 该蛋白在致病机制中发挥核心作用，可作为 PD 治疗的靶点。 未来八年，这款 R35 将为我们提供灵活性和动力来全面调查广泛的 Drp1 参与神经胶质-神经元相互作用、基因-环境介导的神经毒性 该提案利用了与 PD 相关的相互作用和胃细菌。 由经验丰富的研究人员组成的团队采用跨学科方法，并已建立相关 跟踪记录、广泛的化学和遗传工具、高标准技术和 通过功能研究进行分子靶标操作的创新实验模型 该项目的完成将在细胞、回路和整个动物水平上带来范式转变。 我们对 Drp1 如何通过广泛的毒性损伤介导神经毒性的理解。