Gene-Environment Interactions in Neurodegenerative Disease

项目摘要/摘要 与国家环境卫生研究所的任务声明相结合 这项研究的长期目标是确定毒性是否与 广泛使用的含锰/锌-乙烯-二硫代氨基甲酸酯类杀菌剂(锰/锌-EBDC)为 在携带负责细胞抗氧化防御的基因突变的人中加剧 系统和线粒体动态平衡。增加了活性氧物种(ROS)和 线粒体抑制与许多神经退行性疾病有关。另外， 流行病学研究表明，职业性农药暴露会增加许多人的风险 与大脑有关的疾病，尽管单靠暴露往往不足以引起这种疾病 表型。另一方面，特定的基因突变在大约20%的疾病的病因中起作用。 神经退行性疾病(帕金森氏病、阿尔茨海默病等)。因此，很可能是巨大的 大多数患有这些毁灭性疾病的患者的遗传背景导致 更容易受到毒害(基因-环境相互作用)。因此，最重要的是 这一应用的假设是，多次、低剂量暴露于含锰/锌的EBDC 杀菌剂，如代森锰锌，可能会导致带有突变的人群中神经变性的增加 在LRRK2(一种抗氧化防御系统基因)、parkin或PIKN1(两者都与 线粒体有丝分裂或动态平衡)。 为了解决我们的假设，有两个具体目标将指导这项研究。第一个目标是 测定秀丽线虫对多种农药的多重暴露 用于真菌控制的浓度会导致神经退行性变，与单独使用 本实验室发表的暴露研究报告。第二个目标将评估是否暴露于锰/锌-EBDC 杀菌剂对遗传背景改变的生物具有更大的毒性。这些研究将 是通过用与环境相关的浓度的 代森锰锌。我们的目标是描述致命性、神经元变性、 氧化应激和有丝分裂。 这些研究及时地与NIEHS的目标高度相关，因为它们涉及 公众经常接触的高使用杀虫剂的潜在神经毒性 (战略计划主题2)，农用化学品与已知涉及的基因或蛋白质的相互作用 在神经识别方面(战略计划主题2和3)，并为下一个 一代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).