Epigenetic effects of adult and developmental exposure to Parkinsonian toxicants

成人和发育期接触帕金森毒物的表观遗传效应

• 批准号: 9391761
• 负责人: Alison Bernstein
• 金额: $ 24.9万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-01-01 至 2019-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9391761
• 关键词: Adult; Adult Children; Affect; Autopsy; Brain Diseases; Brain region; Chromatin; Cytoplasmic Inclusion; DNA Modification Process; Data; Detection; Development; Dieldrin; Disease; Disease Progression; Dose; Elderly; Elements; Environmental Risk Factor; Epidemiology; Epigenetic Process; Etiology; Evaluation; Exposure to; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Gene-Modified; Genes; Genetic; Genetic Transcription; Genome; Goals; High-Throughput Nucleotide Sequencing; Human; Impairment; Individual; Inherited; Laboratories; Late-Onset Disorder; Link; Mentors; Mentorship; Messenger RNA; Methodology; Methods; Methylation; MicroRNAs; Modeling; Modification; Movement Disorders; Mus; Mutation; National Institute of Environmental Health Sciences; Nerve Degeneration; Neuroanatomy; Neurodegenerative Disorders; Neurons; Output; Oxidative Stress; Parkinson Disease; Parkinsonian Disorders; Patients; Pesticides; Phase; Phenotype; Polychlorinated Biphenyls; Predisposition; Process; Proteins; Regulation; Research; Research Personnel; Risk; Role; Signal Transduction; Small RNA; Substantia nigra structure; System; Techniques; Technology; Testing; Time; Tissue Banks; Tissues; Toxic Environmental Substances; Toxicant exposure; Toxicology; Training; Transcriptional Regulation; Work; acute toxicity; aged; biological adaptation to stress; brain tissue; career; career development; clinical Diagnosis; design; dopamine system; dopaminergic neuron; early life exposure; epidemiology study; epigenetic regulation; epigenome; epigenomics; experience; experimental study; genome wide methylation; genome-wide; human disease; imprint; insight; neuropathology; neurotransmission; nigrostriatal dopaminergic pathway; novel; persistent organic pollutants; pregnant; programs; protein expression; public health relevance; response; toxicant; transcriptome; whole genome

DESCRIPTION (provided by applicant) Parkinson's disease (PD), the most common neurodegenerative movement disorder, is characterized by degeneration of the nigrostriatal dopaminergic pathway and other monoaminergic regions and the formation of cytoplasmic inclusions. The majority of cases of PD are sporadic (i.e. not caused by an inherited monogenic mutation). While the etiology of these sporadic cases remains unclear, it is thought to involve an interaction between genetic and environmental factors. Epidemiological studies suggest that exposure to environmental toxicants increases the risk of PD; many of these compounds have also been associated with PD by post- mortem analysis of brain tissue. The Miller laboratory and others have shown that a variety of these compounds cause oxidative stress and disrupt expression and function of dopaminergic-related and PD-related proteins, resulting in increased susceptibility of dopaminergic neurons to toxicants that target the dopaminergic system in adult and developmental models. It has been proposed that epigenetic modulations could serve as an intermediate process that imprints dynamic environmental experiences on the "fixed" genome, resulting in stable alterations in phenotype. Therefore, it is likely that these factors converge upon the epigenome. In fact, recent work has also revealed a role for regulation of the transcriptome and the epigenome in PD and in the response to toxic exposures. Aberrant gene methylation of PD related genes and deficiencies in microRNAs have been observed in post-mortem PD brains. However, these studies have largely focused on the individual genes responsible for familial PD and not genome-wide changes or in regions or tissues not affected in PD. Moreover, it is not known how these changes in the epigenome are related to changes in neuronal vulnerability. It is possible that epigenomic changes induced by toxicant exposure contribute to neuronal vulnerability by altering expression of proteins within the dopaminergic system. The investigators hypothesize that oxidative stress induced by PD-related toxicants alters epigenetic regulation of genes involved in neurotransmission, the oxidative stress response and those linked to PD, which, in turn, affects the expression of those genes, thereby increasing the vulnerability of dopaminergic neurons and susceptibility to Parkinson's disease. In aim 1 of the mentored phase, the investigators will use high throughput sequencing technology to investigate epigenetic modifications of DNA and changes in the transcriptome in post-mortem tissue from PD patients and controls. In aim 2 of the mentored phase, the investigators will determine how a PD-related toxicant, dieldrin, alters the DNA modifications across the genome and the transcriptome in selective brain regions of mice, including substantia nigra (dopaminergic) and the cortex (non-dopaminergic). In the independent phase (aims 3 and 4), they will assess the effect of developmental exposure to PD-related toxicants on the DNA modifications and the transcriptome in an established mouse toxicological model of dieldrin exposure. This project is designed to develop my research program through mentorship by Dr. Jin, an expert in epigenetics, Dr. Levey, an expert in human neurodegenerative disease, and Dr. Miller, an expert in environmental factors in PD. This application aims to link epigenetic changes with functional outputs of neuronal vulnerability by exploring how exposure to PD-related toxicants affects elements involved in establishing and maintaining gene expression patterns and chromatin state that, in turn, affect dopaminergic function and vulnerability. The Jin laboratory has pioneered novel techniques, including detection of 5-hydroxymethylcytosine, and can examine the entire transcriptome, including small RNAs, and epigenome. These studies would be the first application of these cutting edge epigenetic techniques to toxicological models and enable analysis of these models on a scale not previously possible. Furthermore, this proposal also includes mentoring by Dr. Levey to provide data on epigenetic modifications of DNA in post-mortem tissue from PD patients and controls as well as continued mentoring by Dr. Miller in toxicological methodologies. This will allow for the identification of novel mechanisms of epigenetic regulation in PD and the comparison of changes identified mouse toxicological models with modifications found in human disease. Completion of these aims will contribute to the goals of NIEHS by identifying novel mechanisms of toxicant- induced epigenetic and transcriptional regulation as it relates to PD. These studies will also serve as a starting point for further mechanistic studies of epigenetic processes and the functional consequences of the identified epigenetic changes, with an overall aim of linking developmental exposures with late life disease. Furthermore, this project will provide the training and career development for me to begin my career as an independent researcher.

描述（由申请人提供） 帕金森病（PD）是最常见的神经退行性运动障碍，其特征是黑质纹状体多巴胺能通路和其他单胺能区域的变性以及细胞质包涵体的形成。大多数 PD 病例是散发性的（即不是由遗传性单基因突变引起的）。虽然这些散发病例的病因尚不清楚，但据认为涉及遗传和环境因素之间的相互作用。流行病学研究表明，接触环境毒物会增加患帕金森病的风险；通过对脑组织的尸检分析，其中许多化合物也与帕金森病有关。 Miller 实验室和其他实验室已经证明，这些化合物中的多种会引起氧化应激，并破坏多巴胺能相关蛋白和 PD 相关蛋白的表达和功能，导致成人和发育模型中多巴胺能神经元对针对多巴胺能系统的毒物的敏感性增加。 有人提出，表观遗传调节可以作为一个中间过程，将动态环境经历印在“固定”基因组上，从而导致表型的稳定改变。 因此，这些因素很可能集中在表观基因组上。事实上，最近的工作还揭示了转录组和表观基因组在帕金森病和对有毒暴露的反应中的调节作用。 在死后的帕金森病大脑中观察到帕金森病相关基因的异常基因甲基化和 microRNA 的缺陷。然而，这些研究主要集中于导致家族性帕金森病的个体基因，而不是全基因组变化或未受帕金森病影响的区域或组织。 此外，尚不清楚表观基因组的这些变化与神经元脆弱性的变化有何关系。有毒物质暴露引起的表观基因组变化可能通过改变多巴胺能系统内蛋白质的表达而导致神经元脆弱性。 研究人员推测，帕金森病相关毒物引起的氧化应激会改变参与神经传递、氧化应激反应和帕金森病相关基因的表观遗传调控，进而影响这些基因的表达，从而增加多巴胺能神经元的脆弱性以及对帕金森病的易感性。在指导阶段的目标 1 中，研究人员将使用高通量测序技术来研究 PD 患者和对照死后组织中 DNA 的表观遗传修饰和转录组的变化。 在指导阶段的目标 2 中，研究人员将确定与 PD 相关的毒物狄氏剂如何改变小鼠选择性大脑区域（包括黑质（多巴胺能）和皮质（非大脑皮层））的基因组和转录组 DNA 修饰。多巴胺能）。 在独立阶段（目标 3 和 4），他们将在已建立的狄氏剂暴露小鼠毒理学模型中评估发育期暴露于 PD 相关毒物对 DNA 修饰和转录组的影响。 该项目旨在通过表观遗传学专家 Jin 博士、人类神经退行性疾病专家 Levey 博士和 PD 环境因素专家 Miller 博士的指导来开发我的研究计划。该应用旨在通过探索暴露于帕金森病相关毒物如何影响参与建立和维持基因表达模式和染色质状态的元素，进而影响多巴胺能功能和脆弱性，将表观遗传变化与神经元脆弱性的功能输出联系起来。 Jin实验室开创了新技术，包括检测5-羟甲基胞嘧啶，并且可以检查整个转录组，包括小RNA和表观基因组。这些研究将是这些尖端表观遗传学技术首次应用于毒理学模型，并能够以以前不可能的规模对这些模型进行分析。此外，该提案还包括 Levey 博士的指导，以提供 PD 患者和对照死后组织中 DNA 表观遗传修饰的数据，以及 Miller 博士在毒理学方法学方面的持续指导。这将有助于识别帕金森病表观遗传调控的新机制，并将小鼠毒理学模型的变化与人类疾病中发现的变化进行比较。 通过确定与 PD 相关的毒物诱导的表观遗传和转录调控的新机制，完成这些目标将有助于 NIEHS 的目标。这些研究也将作为进一步的表观遗传过程和机制研究的起点。 已确定的表观遗传变化的功能后果，总体目标是将发育暴露与​​晚年疾病联系起来。此外，该项目还将提供培训 和职业发展，让我开始作为一名独立研究员的职业生涯。