Interactions for Pesticides, mitochondria and genetics in Parkinson's disease.

帕金森病中农药、线粒体和遗传学的相互作用。

基本信息

批准号：
7635654
负责人：
M FLINT BEAL
金额：
$ 48.14万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-21 至 2011-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7635654
关键词：
3,4-Dihydroxyphenylacetic Acid Abbreviations Affect Animal Model Behavioral Biotin Brain Cell Death Cell Line Cell Survival Cells Characteristics Chronic Corpus striatum structure Coupled Cysteine DNA Nucleotidylexotransferase Data Deoxyguanosine Dependovirus Development Disease Dopamine Drug Metabolic Detoxication Environmental Exposure Environmental Risk Factor Epidemiologic Studies Epidemiology Etiology Event Exposure to Gene Mutation Gene Targeting Genetic Genetic Predisposition to Disease Glial Fibrillary Acidic Protein Glutathione S-Transferase Goals Homovanillic Acid Human ITGAM gene Impairment In Situ Nick-End Labeling Inflammation Intervention Knock-out LRRK2 gene Label Lead Ligase Link Maneb Mating Types Metabolic Control Mitochondria Modeling Movement Disorders Mus Mutation NAD(P)H dehydrogenase (quinone) 1, human NADP NADPH Oxidase 1 NF-E2-related factor 2 NQO1 gene Nerve Degeneration Neuraxis Neurodegenerative Disorders Neurons Oral Administration Outcome Oxidative Stress Oxidopamine PARK7 gene PINK1 gene PTGS2 gene Paraquat Parkinson Disease Pathogenesis Pathologic Pathway interactions Peroxisome Proliferator-Activated Receptors Pesticides Phosphotransferases Play Predisposition Reactive Oxygen Species Regulation Regulator Genes Reverse Transcriptase Polymerase Chain Reaction Risk Risk Factors Rodent Role Signal Pathway Signal Transduction Signal Transduction Pathway Substantia nigra structure Superoxide Dismutase System TNF receptor-associated factor 1 Techniques Technology Testing Time Transcriptional Regulation Transgenic Mice Tyrosine 3-Monooxygenase United States Validation cell injury cyclooxygenase 2 dopaminergic neuron gene environment interaction heme oxygenase-1 human NOS2A protein in vivo insight laser capture microdissection leucine-rich repeat kinase 2 loss of function mutation macrophage mitochondrial dysfunction mouse model mtTF1 transcription factor mutant neurodegenerative phenotype neuron loss neuronal survival novel overexpression oxidative damage pars compacta pesticide exposure pesticide interaction pesticide poisoning public health relevance rac1 GTP-Binding Protein synuclein

项目摘要

DESCRIPTION (provided by applicant): Parkinson's disease (PD) is a devastating neurodegenerative disorder characterized by a loss of substantia nigra pars compacta neurons, which currently affects 1.5 million people in the United States. Although rare mutations associated with familial forms of PD have been identified most cases occur sporadically. While the causes of PD are unknown, a critical role of environmental factors either alone, or in combination with genetic susceptibilities is implicated in disease pathogenesis. Major pathologic mechanisms that lead to neurodegenerative phenotype of nigrostriatal dopaminergic neurons include mitochondrial dysfunction, oxidative damage, impairments of key cell survival signaling, and activation of inherent cell death pathways. Epidemiological studies have identified pesticides as potential environmental exposures that influence the risk of PD. Our preliminary data suggest that oral administration of pesticides in mice cause degeneration of nigrostriatal dopaminergic neurons, striatal loss of dopamine and its metabolites, pathologic accumulation of 1-synuclein and oxidative damage. We hypothesize that administration of these pesticides cause neurodegeneration due to mitochondrial dysfunction, and by activation or impairment of signal transduction pathways that are detrimental for normal functioning of dopaminergic neurons. Additionally, these pathologic mechanisms may lead to exacerbation of neurodegeneration in transgenic mouse models of familial PD. Three specific aims are proposed to test the hypothesis. Aim 1 will study the identification and validation of key cell signaling pathways that lead to nigrostriatal dopaminergic neurodegeneration due to pesticide exposure in mice. Aim 2 will study the role of transcriptional regulation of key cell signaling pathways such as Nrf2/ARE, PGC-1 alpha and SIRT1 in addition to specific signal transduction pathways identified and validated in Aim 1 on mitochondrial function and neuropathological features involved in disease development due to pesticide exposure in mice. Aim 3 will examine the role of pesticide exposures in transgenic mouse models of familial PD to assess mitochondrial function, cell signaling pathways leading to exacerbation of nigrostriatal dopaminergic neurons and behavioral abnormalities. These studies will provide us with novel mechanistic insights to events leading to disease development in both sporadic and familial forms of PD due to pesticide exposure and will enable us identify potential links between gene environment interactions in PD. PUBLIC HEALTH RELEVANCE: This study proposes to identify novel signal transduction pathways in wild type and transgenic mice harboring familial PD mutations for onset and development of Parkinson's disease (PD) due to exposure of mitochondria targeted pesticide. The study will enrich and refine our understanding of pesticide-induced cell damage pathways observed in sporadic and familial PD and identify new target(s) for intervention in PD pathogenesis.

描述（由申请人提供）：帕金森病 (PD) 是一种破坏性神经退行性疾病，其特征是黑质致密部神经元丧失，目前影响美国 150 万人。尽管已发现与家族性 PD 相关的罕见突变，但大多数病例都是散发的。虽然帕金森病的病因尚不清楚，但环境因素单独或与遗传易感性相结合，在疾病发病机制中发挥着关键作用。导致黑质纹状体多巴胺能神经元神经退行性表型的主要病理机制包括线粒体功能障碍、氧化损伤、关键细胞生存信号传导受损以及固有细胞死亡途径激活。流行病学研究已确定农药是影响帕金森病风险的潜在环境暴露。我们的初步数据表明，小鼠口服农药会导致黑质纹状体多巴胺能神经元变性、纹状体多巴胺及其代谢物损失、1-突触核蛋白病理性积累和氧化损伤。我们假设施用这些农药会由于线粒体功能障碍以及信号转导途径的激活或损伤而导致神经变性，这不利于多巴胺能神经元的正常功能。此外，这些病理机制可能导致家族性帕金森病转基因小鼠模型神经退行性恶化。提出了三个具体目标来检验该假设。目标 1 将研究关键细胞信号传导途径的识别和验证，这些信号传导途径会导致小鼠因接触农药而导致黑质纹状体多巴胺能神经变性。目标 2 将研究 Nrf2/ARE、PGC-1 α 和 SIRT1 等关键细胞信号传导途径的转录调控作用，以及目标 1 中确定和验证的特定信号转导途径对疾病发展中涉及的线粒体功能和神经病理学特征的作用。小鼠接触农药的情况。目标 3 将研究农药暴露在家族性 PD 转基因小鼠模型中的作用，以评估线粒体功能、导致黑质纹状体多巴胺能神经元恶化和行为异常的细胞信号传导途径。这些研究将为我们提供新的机制见解，了解因接触农药而导致散发性和家族性帕金森病发展的事件，并使我们能够确定帕金森病基因环境相互作用之间的潜在联系。公共健康相关性：本研究旨在确定携带家族性 PD 突变的野生型和转基因小鼠中因暴露于线粒体靶向农药而导致帕金森病 (PD) 发病和发展的新信号转导途径。该研究将丰富和完善我们对散发性和家族性帕金森病中观察到的农药诱导的细胞损伤途径的理解，并确定干预帕金森病发病机制的新靶点。