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: 8767225
• 负责人: Alison Bernstein
• 金额: $ 8.77万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-16 至 2016-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8767225
• 关键词: Acute; Adult; Adult Children; Affect; Autopsy; Brain; Brain region; Chromatin; Cytoplasmic Inclusion; DNA Modification Process; Data; Detection; Development; Dieldrin; Disease; Disease Progression; Dose; Elderly; Elements; Environmental Risk Factor; Epidemiologic Studies; Epidemiology; Epigenetic Process; Etiology; Evaluation; Exposure to; Future; Gene Expression; Gene Expression Profile; Gene Expression Regulation; Genes; Genetic; Genome; Goals; High-Throughput Nucleotide Sequencing; Human; Individual; Inherited; Laboratories; 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; Staging; Substantia nigra structure; System; Techniques; Technology; Testing; Time; Tissue Banking; Tissue Banks; Tissues; Toxic Environmental Substances; Toxic effect; Toxicant exposure; Training; Transcriptional Regulation; Work; aged; biological adaptation to stress; brain tissue; career; career development; clinical Diagnosis; design; dopamine system; dopaminergic neuron; early life exposure; epigenome; epigenomics; experience; genome wide methylation; genome-wide; human disease; imprint; insight; late disease onset; neuropathology; neurotransmission; nigrostriatal dopaminergic pathway; novel; pollutant; pregnant; programs; protein expression; public health relevance; research study; response; toxicant

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的变性以及细胞质内含物的形成。大多数帕金森病是散发性的(即不是由遗传单基因突变引起的)。虽然这些零星病例的病因尚不清楚，但人们认为它涉及遗传和环境因素之间的相互作用。流行病学研究表明，暴露在环境毒物中会增加帕金森病的风险；通过对脑组织的尸检分析，这些化合物中的许多也与帕金森病有关。Miller实验室和其他人已经证明，这些化合物中的各种导致氧化应激，扰乱多巴胺能相关和PD相关蛋白的表达和功能，导致多巴胺能神经元对针对成年和发育模型中的多巴胺能系统的毒物的易感性增加。 有人提出，表观遗传调控可以作为一个中间过程，将动态的环境经验印记在固定的基因组上，导致表型的稳定变化。因此，这些因素很可能集中在表观基因组上。事实上，最近的工作也揭示了帕金森病中转录组和表观基因组的调节以及对毒性暴露的反应。帕金森病相关基因的异常甲基化和microRNAs的缺失已在死后帕金森病患者的脑中观察到。然而，这些研究主要集中在与家族性帕金森病有关的单个基因上，而不是基因组范围的变化，也不是在不影响帕金森病的区域或组织上。此外，尚不清楚表观基因组的这些变化如何与神经元脆弱性的变化有关。毒物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的脆弱性。 研究人员假设，PD相关毒物诱导的氧化应激改变了涉及神经传递、氧化应激反应和与PD相关的基因的表观遗传调节，进而影响这些基因的表达，从而增加了多巴胺能神经元的脆弱性和帕金森氏症的易感性。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调查帕金森病患者和对照组死后组织中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大脑选择性区域的基因组和转录组的DNA修饰，包括黑质(多巴胺能)和皮质(非多巴胺能)。在独立阶段(目标3和4)，他们将评估发育过程中暴露于PD相关毒物对狄氏剂暴露的小鼠毒理学模型中DNA修饰和转录组的影响。 这个项目旨在通过表观遗传学专家金博士、人类神经退行性疾病专家利维博士和帕金森氏病环境因素专家米勒博士的指导来发展我的研究计划。这项应用旨在通过探索暴露于PD相关毒物如何影响建立和维持基因表达模式和染色质状态的元件，进而影响多巴胺能功能和易损性，将表观遗传学变化与神经元脆弱性的功能输出联系起来。金的实验室开创了新技术的先河，包括检测5-羟甲基胞嘧啶，并可以检查整个转录组，包括小RNA和表观基因组。这些研究将是第一次将这些尖端的表观遗传学技术应用于毒理学模型，并使对这些模型的分析达到以前不可能实现的规模。此外，这项建议还包括由Levey博士提供指导，以提供PD患者和对照组死后组织中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，并将识别出的小鼠毒理学模型的变化与人类疾病中发现的修改进行比较。 完成这些目标将有助于通过确定毒物诱导的表观遗传和转录调控的新机制来实现NIEHS的目标，因为它与帕金森病有关。这些研究也将作为进一步表观遗传过程的机制研究的起点 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 和职业发展为我开始作为一名独立研究人员的职业生涯。