Pesticides and Parkinson's Disease

农药与帕金森病

• 批准号: 7902738
• 负责人: ZHENGUI XIA
• 金额: $ 10万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-15 至 2010-08-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7902738
• 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

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(申请人提供)：虽然帕金森病(PD)的病因尚未确定，但流行病学研究表明，PD风险的增加与职业暴露于杀虫剂(包括广泛使用的除草剂百草枯)之间存在相关性。有趣的是，用百草枯治疗的小鼠产生了许多帕金森病的关键特征，包括大脑黑质致密部(SNPC)中的多巴胺能神经元变性和包含包涵体的1-突触核蛋白的形成。因此，对百草枯诱导的多巴胺能神经元死亡的研究可能为调控多巴胺能神经元死亡和存活的机制提供重要的新信息，从而为研究帕金森病的分子基础提供重要的新见解。最近，我们发现百草枯选择性地杀死原代培养的多巴胺能神经元的机制需要激活c-jun氨基末端蛋白激酶(JNK)和JNK诱导的基因表达。此外，碱性成纤维细胞生长因子可抑制百草枯诱导的多巴胺能神经元死亡。这一假设是基于这样的假设，即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起着重要作用，这种细胞死亡可能是由BimEL介导的，并被bFGF拮抗。这些机制研究应该提供关于帕金森病模型中多巴胺能神经元死亡的分子基础的关键信息。此外，我们建议的研究符合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的影响的理解的研究”，目标#2是“使用环境毒物来了解人类生物学的基本机制”。与公共卫生相关的帕金森氏病是第二种最常见的与衰老相关的神经退行性疾病。我们建议在体外和体内阐明百草枯诱导多巴胺能神经元死亡的分子机制。这些机制研究将提供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，并可能为帕金森病的分子基础提供重要的新见解。