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）