Mechanism of Peroxiredoxin 3 in a Model of Pesticide-Mediated Neurodegeneration

过氧化还原蛋白 3 在农药介导的神经变性模型中的作用机制

基本信息

批准号：
8265855
负责人：
James R Roede
金额：
$ 3.32万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-03-01 至 2012-09-25
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8265855
关键词：
4 hydroxynonenal Affect Aldehydes Alkylation Americas Antioxidants Apoptosis Apoptotic Biological Assay Brain Catecholamines Cell Death Cells Chemicals Chemosensitization Copper Data Development Drug Metabolic Detoxication Environmental Exposure Epidemiology Exposure to Foundations Future Genetic Glutathione Herbicides Human Hydrogen Peroxide In Vitro Industrial fungicide Injury Investigation Knowledge Link Lipid Peroxidation MAP3K5 gene Maneb Manganese Mass Spectrum Analysis Measures Mediating Metabolic Metabolism Methods Midbrain structure Mitochondria Modeling Movement Disorders Mus Nerve Nerve Degeneration Neurons Organ Outcome Oxidants Oxidation-Reduction Oxidative Stress Oxidoreductase PRDX3 peroxidase Paraquat Parkinson Disease Pathogenesis Pathway interactions Permeability Peroxidases Peroxides Pesticides Poison Population Proteins Proteome Proteomics Research Research Support Risk Role Sampling Substantia nigra structure System Testing Thioredoxin-2 Tissues Toxic effect Transgenic Mice Translating Translations Work adduct aldehyde dehydrogenases base biological adaptation to stress design dopaminergic neuron environmental pesticide exposure farm worker in vivo in vivo Model innovation metabolomics mouse model neurotoxicity oxidation oxidative damage pesticide exposure research study response

项目摘要

DESCRIPTION (provided by applicant): Environmental pesticide exposure is connected to the occurrence of Parkinson's disease (PD), the most common neurodegenerative movement disorder in America. Epidemiological investigations indicate exposure to the pesticides paraquat (PQ) and maneb (MB) increase the risk of PD, but the underlying mechanisms are unknown. Mitochondrial oxidative stress appears to be central to environmental causes of PD, which is supported by research on the antioxidant glutathione (GSH). However, recent data show that peroxiredoxin 3 (Prx3), a peroxidase supported by the antioxidant thioredoxin-2 (Trx2), has a predominant role in mitochondrial peroxide metabolism. Oxidation of Trx2 activates cell death mechanisms through the mitochondrial permeability transition and activation of apoptosis signal regulating kinase-1 (ASK1). The proposed research is designed to investigate the hypothesis that the Trx2/Prx3 system is an important mitochondrial antioxidant system in the substatntia nigra that is disrupted by MB-potentiated PQ toxicity. To accomplish this, two specific aims consisting of in vitro and in vivo models will be used. In Aim 1, dopaminergic SH-SY5Y cells will be treated with PQ, MB or in combination to evaluate stress responses, potentiation of Trx2/Prx3 oxidation and activation of cell death pathways. This research will involve specific mechanistic targets of mitochondria and mass spectrometry-based proteomic analyses. To examine MB-mediated effects, aldehyde dehydrogenase activity and intracellular copper accumulation will be measured. In Aim 2, a genetic mouse model (Prx3 over- expressing mouse) will be used to study specific mitochondrial redox effects of PQ + MB in vivo. Abundance and compartmental redox effects will be measured by mass spectrometry-based proteomics and discovery- based metabolomic analyses. This research will provide a foundation for future translation of results into human studies, where archival samples from exposed farm workers are available. Lastly, these studies will advance the understanding of the mechanistic role of the Trx2/Prx3 system in pesticide-mediated neurodegeneration.

描述（由申请人提供）：环境农药暴露与帕金森病（PD）的发生有关，帕金森病是美国最常见的神经退行性运动障碍。流行病学调查表明，接触杀虫剂百草枯 (PQ) 和代森锰 (MB) 会增加患 PD 的风险，但其潜在机制尚不清楚。线粒体氧化应激似乎是 PD 环境原因的核心，抗氧化剂谷胱甘肽 (GSH) 的研究也支持了这一点。然而，最近的数据表明，过氧化还原蛋白 3 (Prx3) 是一种由抗氧化剂硫氧还蛋白 2 (Trx2) 支持的过氧化物酶，在线粒体过氧化物代谢中起主导作用。 Trx2 的氧化通过线粒体通透性转变和凋亡信号调节激酶 1 (ASK1) 的激活来激活细胞死亡机制。拟议的研究旨在调查以下假设：Trx2/Prx3 系统是黑质中重要的线粒体抗氧化系统，该系统会被 MB 增强的 PQ 毒性破坏。为了实现这一目标，将使用由体外和体内模型组成的两个特定目标。在目标 1 中，将用 PQ、MB 或组合处理多巴胺能 SH-SY5Y 细胞，以评估应激反应、Trx2/Prx3 氧化的增强和细胞死亡途径的激活。这项研究将涉及线粒体的特定机制目标和基于质谱的蛋白质组分析。为了检查 MB 介导的作用，将测量乙醛脱氢酶活性和细胞内铜积累。在目标 2 中，将使用遗传小鼠模型（Prx3 过表达小鼠）来研究 PQ + MB 在体内的特定线粒体氧化还原效应。丰度和区室氧化还原效应将通过基于质谱的蛋白质组学和基于发现的代谢组学分析来测量。这项研究将为未来将结果转化为人体研究奠定基础，其中可以获得来自暴露农场工人的档案样本。最后，这些研究将增进对 Trx2/Prx3 系统在农药介导的神经变性中的机制作用的理解。