Gene-Environment Interactions in Neurodegenerative Disease

神经退行性疾病中的基因-环境相互作用

• 批准号: 9304681
• 负责人: VANESSA A FITSANAKIS
• 金额: $ 46.8万
• 依托单位: NORTHEAST OHIO MEDICAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9304681
• 关键词: Acids; Address; Affect; Agricultural Workers; Agriculture; Agrochemicals; Alzheimer' s Disease; Antioxidants; Brain; Caenorhabditis elegans; DNA Sequence Alteration; Data; Disease; Dose; Ethylenes; Etiology; Exposure to; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Goals; Health; Homeostasis; Human; Individual; Industrial fungicide; Knowledge; LRRK2 gene; Lead; Light; Link; Literature; Mission; Mitochondria; Modeling; Mutation; National Institute of Environmental Health Sciences; Nerve Degeneration; Nervous system structure; Neurodegenerative Disorders; Occupational; Organism; Oxidative Stress; PINK1 gene; Parkinson Disease; Patients; Persons; Pesticides; Play; Population; Production; Proteins; Public Health; Publishing; Reactive Oxygen Species; Research; Risk; Role; Scientist; Strategic Planning; System; Testing; Time; Toxic Environmental Substances; Toxic effect; Training; Training and Education; United States; Work; base; brain cell; disease phenotype; environmental agent; epidemiology study; gene environment interaction; improved; insight; mancozeb; member; neuron loss; neuropathology; neurotoxicity; next generation; novel; parkin gene/protein; pesticide exposure; prevent; science teacher; therapy design; undergraduate student

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).

项目摘要/摘要 结合国家环境卫生研究所的任务声明 科学（NIEHS），这项研究的长期目标是确定是否与 含有Mn/Zn-乙烯 - 双甲甲酸酯（MN/ZN-EBDC）的广泛使用的真菌类别为 与负责细胞抗氧化剂防御的基因相关的突变患者加剧 系统和线粒体稳态。活性氧（ROS）和 在许多神经退行性疾病中隐含线粒体抑制。此外， 流行病学研究表明，占用农药的暴露会增加一个人对许多人的风险 与大脑相关的疾病，尽管仅凭暴露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％的病因中起作用 神经退行性病例（帕金森氏病，阿尔茨海默氏病等）。那很可能是疫苗 大多数患有这些毁灭性疾病的患者具有遗传背景，导致 更大的脆弱性（基因 - 环境相互作用）。因此，总体 该应用的假设是多次低剂量暴露于Mn/Zn-EBDC的 杀菌剂（例如Mancozeb）可能导致突变种群中的神经退行性增加 在LRRK2（抗氧化剂防御系统基因）中，Parkin或Pikn1（两者都与 线粒体线粒体或稳态）。 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 确定秀丽隐杆线虫（秀丽隐杆线虫）是否多次暴露于各种农药 用于真菌控制的浓度导致神经变性类似于单一观察到的神经变性 该实验室发表的暴露研究。第二个目标将评估是否接触MN/ZN-EBDC 杀菌剂会导致具有改良遗传背景的生物体的毒性更大。这些研究会 通过以环境相关的浓度处理各种秀丽隐杆线虫来完成 Mancozeb。目的是表征致死性，神经元变性的潜力增加， 氧化应激和线粒体。 这些研究与NIEH的目标及时且高度相关，因为它们解决了 高使用农药的潜在神经毒性常规暴露于公众 （战略计划主题2），农业化学物质与已知所涉及的基因或蛋白质的相互作用 在神经退行性方面（战略计划主题2和3），并向下一个提供教育和培训 科学家和科学专业人士的一代（战略计划主题5）。