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).

项目概要/摘要 结合国家环境健康研究所的使命宣言 科学（NIEHS），这项研究的长期目标是确定毒性是否与 广泛使用的含有 Mn/Zn-亚乙基双二硫代氨基甲酸酯 (Mn/Zn-EBDC) 的杀菌剂是 在具有与负责细胞抗氧化防御的基因相关的突变的人中，这种情况会加剧 系统和线粒体稳态。 线粒体抑制与许多神经退行性疾病有关。 流行病学研究表明，接触农药会增加一个人罹患多种疾病的风险 与大脑相关的疾病，尽管单独接触通常不足以引起疾病 另一方面，特定基因突变在约 20% 的病因中发挥作用。 神经退行性疾病（帕金森病、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都有遗传背景，导致 因此，更容易受到有毒伤害（基因与环境的相互作用）。 该应用的假设是多次低剂量暴露于含 Mn/Zn-EBDC 的环境中 杀菌剂，如代森锰锌，可能会导致突变人群的神经变性加剧 LRRK2（一种抗氧化防御系统基因）、parkin 或 PIKN1（两者均与 线粒体自噬或稳态）。 为了解决我们的假设，有两个具体目标将指导研究。 确定秀丽隐杆线虫（C. elegans）是否多次暴露于各种农药 用于真菌控制的浓度会导致神经变性，类似于在单一药物中观察到的情况 该实验室发表的暴露研究的第二个目标是评估是否暴露于 Mn/Zn-EBDC。 这些研究将导致杀菌剂对遗传背景改变的生物体产生更大的毒性。 通过用环境相关浓度的线虫处理各种菌株来完成 代森锰锌的目标是描述致死率、神经变性、 氧化应激和线粒体自噬。 这些研究是及时的并且与 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农药的潜在神经毒性 （战略计划主题 2）农用化学品与已知相关基因或蛋白质的相互作用 神经退行性疾病（战略计划主题 2 和 3），并为下一代提供教育和培训 一代科学家和科学专业人员（战略计划主题 5）。