Pathogenic Mechanisms of Environmental Toxicants in Parkinson's Disease

环境毒物对帕金森病的致病机制

基本信息

批准号：
7616565
负责人：
LIAN LI
金额：
$ 34.88万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-05-01 至 2013-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7616565
关键词：
Accounting Animals Behavioral Biochemical Biological Brain Brain region Cell Survival Cells Cultured Cells Data Dieldrin Disease Environment Environmental Risk Factor Epidemiologic Studies Etiology Exposure to Gene Mutation Genes Genetic Goals Human Inherited Knock-out Lead Link Mediating Modeling Modification Molecular Molecular Genetics Movement Disorders Mutant Strains Mice Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Oxidation-Reduction Oxidative Stress Paper Paraquat Parkinson Disease Pathogenesis Pathway interactions Patients Pesticides Phenotype Play Predisposition Proteins Proteomics Publishing Reactive Oxygen Species Research Risk Risk Factors Role Rotenone Series Site Site-Directed Mutagenesis Structure Substantia nigra structure Testing Toxic Environmental Substances Transgenic Mice animal model development dopaminergic neuron early onset effective therapy gene environment interaction in vivo insight meetings mouse model mutant neuron loss nigrostriatal system novel oxidation oxidative damage prevent public health relevance toxicant

Accounting Animals Behavioral Biochemical Biological Brain Brain region Cell Survival Cells Cultured Cells Data Dieldrin Disease Environment Environmental Risk Factor Epidemiologic Studies Etiology Exposure to Gene Mutation Genes Genetic Goals Human Inherited Knock-out Lead Link Mediating Modeling Modification Molecular Molecular Genetics Movement Disorders Mutant Strains Mice Mutation Nature Nerve Degeneration Neurodegenerative Disorders Neuronal Dysfunction Oxidation-Reduction Oxidative Stress Paper Paraquat Parkinson Disease Pathogenesis Pathway interactions Patients Pesticides Phenotype Play Predisposition Proteins Proteomics Publishing Reactive Oxygen Species Research Risk Risk Factors Role Rotenone Series Site Site-Directed Mutagenesis Structure Substantia nigra structure Testing Toxic Environmental Substances Transgenic Mice animal model development dopaminergic neuron early onset effective therapy gene environment interaction in vivo insight meetings mouse model mutant neuron loss nigrostriatal system novel oxidation oxidative damage prevent public health relevance toxicant

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项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is the most common neurodegenerative movement disorder characterized by progressive degeneration of dopaminergic neurons in the substantia nigra. The etiology of PD remains unknown. Epidemiological studies have revealed that exposure to environmental toxicants, including pesticides, increases the risk of PD. Many of these toxicants, such as rotenone, paraquat, and 1-methyl-4- phenyl-1,2,3,6-tetrahydropyridine (MPTP), have been shown to increase the levels of reactive oxygen species (ROS) and cause PD-like phenotypes in animals. These and other lines of evidence have implicated a crucial role for oxidative stress in PD pathogenesis. However, it is not known how environmental toxicant-induced oxidative stress leads to neuronal dysfunction and, ultimately, neuronal cell death. The long-term goal of this research is to elucidate the molecular mechanisms by which environmental toxicants cause neurodegeneration in PD. While only a very small percentage of PD cases are monogenic familial forms, molecular characterization of the identified familial PD proteins has revealed novel pathways involved in PD pathogenesis. DJ-1 is a recently identified PD gene whose mutations cause an early-onset, autosomal recessive form of familial PD. Accumulating evidence indicates that DJ-1 plays an essential role in protecting dopaminergic neurons against oxidative stress. This project will investigate the interaction between the familial PD gene DJ-1 and sporadic PD-associated environmental toxicants, and test the hypothesis that environmental toxicants cause oxidative damage to DJ-1, thereby contributing to the pathogenesis of sporadic PD in a manner similar to DJ-1 genetic mutations in causing familial PD. A combination of biochemical, proteomic, biophysical, cell biological, and molecular genetic approaches will be used to characterize the environmental toxicant-induced oxidative damage to DJ-1, examine the in vivo role of environmental toxicant-induced DJ-1 oxidation in PD pathogenesis, and determine the mechanisms by which environmental toxicants disrupt the DJ-1 neuroprotective pathway. Completion of this project should advance our understanding of the mechanistic role of environmental toxicants in neurodegeneration and help develop more effective therapies to treat PD. PUBLIC HEALTH RELEVANCE Project Narrative Although the etiology of Parkinson's disease (PD) remains unknown, there is compelling evidence that environmental toxicants, especially pesticides, are dominant risk factors in sporadic PD. The goal of the proposed research is to determine how environmental toxicants lead to neuronal dysfunction and, ultimately, neuronal cell death in PD. The results of the proposed studies will promote the discovery of new therapies for preventing and treating this devastating illness.

描述（由申请人提供）：帕金森氏病（PD）是最常见的神经退行性运动障碍，其特征是黑质中多巴胺能神经元进行性变性。 PD的病因仍然未知。流行病学研究表明，包括农药在内的环境有毒物质的暴露会增加PD的风险。这些毒物中的许多，例如烤面包酮，paraquat和1-甲基-4-苯基-1,2,3,6-四氢吡啶（MPTP），已被证明会增加动物中的活性氧（ROS）的水平，并引起PD样表型。这些证据和其他证据暗示了氧化应激在PD发病机理中的关键作用。然而，尚不清楚环境毒性诱导的氧化应激如何导致神经元功能障碍，并最终导致神经元细胞死亡。这项研究的长期目标是阐明环境有毒物质在PD中引起神经变性的分子机制。尽管只有很小的PD病例是单基因家族性形式，但鉴定出的家族性PD蛋白的分子表征揭示了与PD发病机理有关的新途径。 DJ-1是最近鉴定出的PD基因，其突变引起了家族性PD的早期发作，常染色体隐性形式。积累的证据表明，DJ-1在保护多巴胺能神经元免受氧化应激方面起着至关重要的作用。该项目将研究家族性PD基因DJ-1与零星PD相关的环境有毒物质之间的相互作用，并检验了以下假说：环境有毒物质对DJ-1造成氧化损害，从而导致与DJ-1遗传突变相似，从而导致零星PD的发病机理，从而导致家族性家庭中的DJ-1遗传突变。生化，蛋白质组学，生物物理，细胞生物学和分子遗传方法的结合将用于表征环境毒物诱导的DJ-1氧化损伤，检查环境毒性毒性诱导的DJ-1氧化在PD病原体中的体内作用，并确定环境毒理中的机构DJ Diss diss diss diss diss diss diss diss diss diss diss diss diss diss diss diss diss diss diss diss diss。该项目的完成应提高我们对环境有毒物质在神经变性中的机械作用的理解，并有助于开发更有效的治疗PD疗法。公共卫生相关性项目叙事尽管帕金森氏病（PD）的病因尚不清楚，但有令人信服的证据表明，环境毒物，尤其是农药，是零星PD的主要危险因素。拟议的研究的目的是确定环境有毒物质如何导致神经元功能障碍，并最终导致PD中的神经元细胞死亡。拟议研究的结果将促进发现新疗法，以预防和治疗这种毁灭性疾病。