Gene-Environment Interactions in Neurodegenerative Disease

项目概要/摘要 结合国家环境卫生研究所的使命声明 科学（NIEHS），这项研究的长期目标是确定是否与毒性相关的 广泛使用的一类含有Mn/Zn-亚乙基-双-二硫代氨基甲酸酯（Mn/Zn-EBDC）的杀真菌剂是 在与细胞抗氧化防御基因相关的突变人群中加剧 系统和线粒体稳态。活性氧（ROS）的含量增加， 线粒体抑制与许多神经变性疾病有关。此外，本发明还 流行病学研究表明，职业性农药暴露会增加一个人的风险， 与大脑有关的疾病，尽管单独接触通常不足以引起疾病 表型。另一方面，特定的基因突变在约20%的患者的病因中起作用。 神经退行性疾病（帕金森病，阿尔茨海默病等）。或许，这是一个巨大的。 大多数患有这些毁灭性疾病的患者都有遗传背景， 更容易受到有毒物质的伤害（基因-环境相互作用）。因此， 本申请的假设是多次低剂量暴露于含Mn/Zn-EBDC 杀真菌剂，如代森锰锌，可能导致突变人群的神经退行性变增加 在LRRK 2（一种抗氧化防御系统基因）、parkin或PIKN 1（两者都与 线粒体自噬或体内平衡）。 为了解决我们的假设，两个具体的目标将指导研究。第一个目标将 确定是否多次暴露秀丽隐杆线虫（C. elegans）对各种杀虫剂 用于真菌控制的浓度导致类似于在单个细胞中观察到的神经变性。 实验室发表的暴露研究第二个目标是评估暴露于Mn/Zn-EBDC是否 杀真菌剂在具有改变的遗传背景的生物体中导致更大的毒性。这些研究将 通过处理各种C.与环境相关的浓度， 代森锰锌目标是描述潜在的致命性增加，神经元变性， 氧化应激和线粒体自噬。 这些研究是及时的，与NIEHS的目标高度相关，因为它们解决了 公众经常接触的高用量杀虫剂的潜在神经毒性 （战略计划主题2），农用化学品与已知参与的基因或蛋白质的相互作用 在神经退化（战略计划主题2和3），并提供教育和培训，以下一个 培养科学家和科学专业人员（战略计划主题5）。

Project Summary/Abstract In conjunction with the Mission Statement of the National Institute of Environmental Health Sciences (NIEHS), the long-term goal of this research is to determine whether toxicity associated with the widely-used class of fungicides containing Mn/Zn-ethylene-bis-dithiocarbamate (Mn/Zn-EBDC) is exacerbated in people with mutations associated with genes responsible for cellular antioxidant defense systems and mitochondrial homeostasis. Increased amounts of reactive oxygen species (ROS) and mitochondrial inhibition are implicated in many neurodegenerative diseases. Additionally, epidemiology studies indicate that occupational pesticide exposure increases a person’s risk for many diseases associated with the brain, although exposure alone is often insufficient to cause the disease phenotype. On the other hand, specific gene mutations play a role in the etiology of about 20% of the neurodegenerative cases (Parkinson’s disease, Alzheimer’s disease, etc.). Thus, it is likely that the vast majority of patients suffering from these devastating diseases had a genetic background that resulted in a greater vulnerability to a toxic insult (gene-environment interaction). Therefore, the overarching hypothesis of this application is that multiple, low-dose exposures to Mn/Zn-EBDC-containing fungicides, such as mancozeb, may lead to increased neurodegeneration in populations with mutations in LRRK2 (an antioxidant defense system gene), parkin, or PIKN1 (both of which are associated with mitochondrial mitophagy or homeostasis). In order to address our hypothesis, two specific aims will guide the research. The first aim will determine if multiple exposures of Caenorhabditis elegans (C. elegans) to various pesticide concentrations used for fungal control leads to neurodegeneration similar to that observed in single exposure studies published by this lab. The second aim will assess whether exposure to a Mn/Zn-EBDC fungicide leads to greater toxicity in organisms with modified genetic backgrounds. These studies will be completed by treating various strains of C. elegans with environmentally-relevant concentrations of mancozeb. The goal is to characterize the potential increases in lethality, neuronal degeneration, oxidative stress, and mitophagy. These studies are timely and highly relevant to the goals of the NIEHS because they address the potential neurotoxicity of high-use pesticides to which members of the public are routinely exposed (Strategic Plan Theme 2), the interaction of agrochemicals with genes or proteins known to be involved in neurodegneration (Strategic Plan Themes 2 & 3), and to provide education and training to the next generation of scientists and science professionals (Strategic Plan Theme 5).