Pesticides and Parkinson's Disease

农药与帕金森病

基本信息

批准号：
7878572
负责人：
ZHENGUI XIA
金额：
$ 34.75万
依托单位：
UNIVERSITY OF WASHINGTON
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：
2008-08-15 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7878572
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Ablation Apoptotic Attenuated Brain Brain-Derived Neurotrophic Factor Cell Death Cessation of life Complement Data Disease Dopaminergic Cell Drug Delivery Systems Epidemiologic Studies Etiology Exposure to Extracellular Signal Regulated Kinases Fibroblast Growth Factor 2 Figs - dietary GDNF gene Gene Expression Goals Herbicides Human Biology In Vitro Inclusion Bodies Isoenzymes JUN gene MAPK10 gene Mediating Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinase Kinases Mitogen-Activated Protein Kinases Modeling Molecular Mus Muscle Cells N-terminal National Institute of Environmental Health Sciences Nerve Degeneration Neurodegenerative Disorders Neurons Occupational Exposure PC12 Cells Paraquat Parkinson Disease Pathogenesis Pesticides Phenylalanine Phosphorylation Play Protein Family Protein Isoforms Protein Kinase Proteins RNA Interference RPS6KA gene Reporter Research Research Support Resistance Risk Role Signal Transduction Signal Transduction Pathway Small Interfering RNA Stimulus Strategic Planning Substantia nigra structure Technology Testing Toxic Environmental Substances Toxic effect Tyrosine 3-Monooxygenase Withdrawal age related base dopaminergic neuron enhancing factor improved in vivo insight interest killings lentiviral-mediated meetings motor deficit neuron apoptosis neuron loss neuroprotection neurotrophic factor pars compacta pro-apoptotic protein promoter public health relevance relating to nervous system response ribosomal protein S6 kinase 2 synuclein

项目摘要

DESCRIPTION (provided by applicant): Although the etiology of Parkinson's disease (PD) has not been defined, epidemiological studies have indicated a correlation between increased risk for PD and occupational exposure to pesticides including paraquat, a widely used herbicide. Interestingly, treatment of mice with paraquat produces many key features of PD including dopaminergic neuron degeneration in the substantia nigra pars compacta (SNpc) of the brain and formation of 1-synuclein containing inclusion bodies. Therefore, studies of paraquat-induced dopaminergic neuron death may provide important new information concerning mechanisms governing the death and survival of dopaminergic neurons and thereby provide important new insights concerning the molecular basis of PD. Recently, we discovered that paraquat selectively kills dopaminergic neurons in primary cultures by a mechanism that requires activation of the c-Jun NH2-terminal protein kinase (JNK) and JNK-induced gene expression. Furthermore, paraquat-induced dopaminergic neuron death is inhibited by bFGF. This proposal is based upon the hypothesis that JNK, specifically the neurospecific JNK3 isoform, plays an important role in paraquat-induced death of dopaminergic neurons, and that this cell death may be mediated by BimEL and antagonized by bFGF. These mechanistic studies should provide critical information concerning the molecular basis of dopaminergic neuron death in the paraquat model of PD. Furthermore, our proposed research meets the goals of NIEHS strategic plan, especially to "support research that improves our understanding of signal transduction pathways and their influence on disease" under goal #2, which is to "use environmental toxicants to understand basic mechanisms in human biology". PUBLIC HEALTH RELEVANCE Parkinson's disease is the second most common aging-related neurodegenerative disorder. We propose to elucidate molecular mechanisms underlying paraquat-induced dopaminergic neuron death in vitro and in vivo. These mechanistic studies should provide critical information concerning the molecular basis of dopaminergic neuron death in the paraquat model of Parkinson's disease, and may provide important new insights concerning the molecular basis Parkinson's disease.

描述（由申请人提供）：虽然帕金森病 (PD) 的病因尚未明确，但流行病学研究表明帕金森病风险增加与职业接触农药（包括广泛使用的除草剂百草枯）之间存在相关性。有趣的是，用百草枯治疗小鼠会产生帕金森病的许多关键特征，包括大脑黑质致密部 (SNpc) 的多巴胺能神经元变性以及含有 1-突触核蛋白的包涵体的形成。因此，对百草枯诱导的多巴胺能神经元死亡的研究可能提供有关控制多巴胺能神经元死亡和存活的机制的重要新信息，从而提供有关PD分子基础的重要新见解。最近，我们发现百草枯通过一种需要激活 c-Jun NH2 末端蛋白激酶 (JNK) 和 JNK 诱导的基因表达的机制选择性地杀死原代培养物中的多巴胺能神经元。此外，bFGF 还可抑制百草枯诱导的多巴胺能神经元死亡。该提议基于以下假设：JNK，特别是神经特异性 JNK3 亚型，在百草枯诱导的多巴胺能神经元死亡中发挥重要作用，并且这种细胞死亡可能由 BimEL 介导并被 bFGF 拮抗。这些机制研究应提供有关 PD 百草枯模型中多巴胺能神经元死亡的分子基础的关键信息。此外，我们提出的研究符合 NIEHS 战略计划的目标，特别是在目标 2 下“支持提高我们对信号转导途径及其对疾病影响的理解的研究”，即“利用环境毒物来了解人类的基本机制”。生物学”。公共卫生相关性帕金森病是第二常见的与衰老相关的神经退行性疾病。我们建议阐明百草枯在体外和体内诱导多巴胺能神经元死亡的分子机制。这些机制研究应提供有关帕金森病百草枯模型中多巴胺能神经元死亡的分子基础的关键信息，并可能提供有关帕金森病分子基础的重要新见解。