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） 帕金森氏病（PD）是最常见的神经退行性运动障碍，其特征在于黑质纹状体多巴胺能途径和其他单胺能区域的变性以及细胞质夹杂物的形成。大多数PD病例都是零星的（即不是由遗传的单基因突变引起的）。尽管这些零星病例的病因尚不清楚，但人们认为涉及遗传因素和环境因素之间的相互作用。流行病学研究表明，暴露于环境有毒物质会增加PD的风险。这些化合物中的许多也通过脑组织的验尸分析与PD有关。米勒实验室和其他实验室表明，各种这些化合物会导致氧化应激，并破坏与多巴胺能相关和PD相关蛋白的表达和功能，从而增加对毒性的毒性敏感性增加，以靶向成人和发展模型中多巴胺能系统的毒性。 已经提出，表观遗传调节可以用作中间过程，在“固定”基因组上烙印动态环境体验，从而导致表型的稳定变化。 因此，这些因素可能会融合表观基因组。实际上，最近的工作还揭示了调节转录组和PD中的表观基因组的作用以及对有毒暴露的反应。 在验尸后的PD脑中已经观察到了与PD相关基因的异常基因甲基化和microRNA中的缺陷。但是，这些研究主要集中在负责家族性PD的单个基因上，而不是全基因组变化或PD不影响的区域或组织中。 此外，尚不清楚表观基因组中的这些变化与神经元脆弱性的变化有关。通过改变多巴胺能系统中蛋白质的表达，毒性暴露引起的表观基因组变化可能导致神经元脆弱性。 研究人员假设由PD相关毒物引起的氧化应激改变了与神经传递，氧化应激反应以及与PD相关的基因的表观遗传调节，从而影响了这些基因的表达，从而增加了多巴胺神经元和易感性对帕克森病的脆弱性。在指导阶段的AIM 1中，研究人员将使用高通量测序技术研究DNA的表观遗传修饰以及PD患者和对照组的死亡后组织中转录组的变化。 在指导阶段的AIM 2中，研究人员将确定与PD相关的毒物Dieldrin如何改变整个基因组的DNA修饰和小鼠选择性大脑区域中的转录组，包括Nigra（多巴胺能）（多巴胺能）和皮质（非多巴胺能）。 在独立阶段（目标3和4），他们将评估与PD相关毒物的发育暴露对DNA修饰的影响以及在dieldrin暴露的既定小鼠毒理学模型中的转录组。 该项目旨在通过表观遗传学专家Jin博士通过指导来制定我的研究计划，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。该应用程序旨在通过探索暴露于PD相关的毒物如何影响参与建立和维持基因表达模式和染色质涉及的元素，将表观遗传变化与神经元脆弱性的功能输出联系起来，从而影响多巴胺能功能和脆弱性。 Jin实验室已经开创了新技术，包括检测5-羟基甲基胞嘧啶，并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技术在毒理学模型中的首次应用，并能够以先前不可能对这些模型进行分析。此外，该提案还包括Levey博士的指导，以提供有关PD患者和对照组验尸组织中DNA的表观遗传修饰的数据，以及Miller博士在毒理学方法论中的继续指导。这将允许鉴定PD表观遗传调节的新机制，并比较确定的小鼠毒理学模型与人类疾病中发现的修饰的变化。 这些目标的完成将通过确定与PD相关的毒物诱导的表观遗传和转录调节的新机制来促进NIEH的目标。这些研究还将成为进一步的表观遗传过程和 确定的表观遗传变化的功能后果，总体目的是将发育暴露与​​后期生命疾病联系起来。此外，该项目将提供培训 我的职业发展使我开始从事独立研究人员的职业生涯。