Diversity Supplement to Dieldrin-induced differential gene methylation and parkinsonian toxicity (R01ES031237)

狄氏剂诱导的差异基因甲基化和帕金森毒性的多样性补充 (R01ES031237)

• 批准号: 10847611
• 负责人: Alison Bernstein
• 金额: $ 2.9万
• 依托单位: RUTGERS BIOMEDICAL AND HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2025-10-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10847611
• 关键词: Adult; Affect; Award; Biological; Candidate Disease Gene; Cell Culture Techniques; DNA Modification Process; Data; Development; Dieldrin; Disease; Disease susceptibility; Elderly; Environment; Environmental Risk Factor; Epigenetic Process; Etiology; Exposure to; Funding; Gene Expression; Genes; Genetic; Goals; Health; In Vitro; Individual; Inherited; Injections; Joints; Link; Mediator; Methylation; Mission; Modeling; Modification; Mus; Mutation; National Institute of Environmental Health Sciences; Neurons; Parkinson Disease; Parkinsonian Disorders; Pathogenesis; Persons; Phenotype; Play; Predisposition; Presynaptic Terminals; Research; Risk; Role; Sampling; Students; System; Testing; Toxic effect; Toxicology; Universities; alpha synuclein; candidate identification; cell type; dopaminergic neuron; epidemiology study; epigenome; experimental study; in vivo; in vivo Model; male; methylation pattern; novel; organochlorine pesticide; parent grant; parent project; pesticide exposure; pre-formed fibril; programs; response; sex; sporadic Parkinson' s Disease; synaptic function; tool; toxicant; transcriptome sequencing

Parent Project Summary The majority of Parkinson’s disease (PD) cases are not caused by an inherited monogenic mutation and disease etiology involves a combination of genetic and environmental factors. Epidemiological studies show that pesticide exposure, particularly to organochlorine pesticides such as dieldrin, increases risk of sporadic PD. In a model of increased PD susceptibility, mice exposed to dieldrin during development show male-specific increased susceptibility to adult exposure to the dopaminergic toxicant MPTP and, in new data from our NIEHS-funded R21, α-synuclein (α-syn) preformed fibrils (PFFs). The epigenome is a potential mediator of this relationship between developmental exposures, increased neuronal vulnerability, and adult disease. In line with this idea, we recently identified sex-specific differential methylation patterns in response to developmental dieldrin exposure. We hypothesize that dieldrin-induced epigenetic modifications during development cause changes in gene expression and phenotype that persist into adulthood, altering the sensitivity to parkinsonian insults and contributing to the development of PD. To test this hypothesis, we will determine cell-type specific DNA modifications and expression profiles of previously identified candidate genes in the dieldrin model (Aim 1); analyze the function of synaptic terminals in our novel dieldrin/PFF two-hit model (Aim 2); and determine if dieldrin or altered expression of candidate genes affects susceptibility to α-syn PFFs in a dopaminergic neuron cell culture model (Aim 3). The long-term goal of these experiments is to determine whether dieldrin-associated differentially methylated genes play a functional role in the biological response to parkinsonian toxicity. Completion of these aims will further the mission of NIEHS to increase our understanding of how the environment affects people in order to promote healthier lives, with a specific project goal of connecting exposures with functional changes in gene expression, neuronal phenotype, and PD susceptibility. The experiments proposed here will help to establish a biological mechanism linking developmental exposure to late life disease. This project will also expand our repertoire of tools for interrogating the function of epigenetic changes by establishing an in vitro experimental paradigm to connect specific epigenetic mechanisms with parkinsonian toxicity. With our in vivo model that combines developmental exposure with adult PFF injections, we will have a set of experimental systems in place that will allow us to test a wide variety of exposures, as well as combinations of exposures, both in vivo and in vitro. Together, this suite of tools will enable us to explore the mechanisms by which PD- related exposures alter neuronal vulnerability in PD, furthering the goal of NIEHS to understand how combined exposures affect disease pathogenesis and individual susceptibility.

父项目摘要 大多数帕金森病（PD）病例不是由遗传性单基因突变引起的， 疾病病因学涉及遗传和环境因素的组合。流行病学研究表明 接触农药，特别是接触狄氏剂等有机氯农药， 警局在PD易感性增加的模型中，在发育期间暴露于狄氏剂的小鼠显示出雄性特异性PD易感性。 成人暴露于多巴胺能毒物MPTP的易感性增加， NIEHS资助的R21，α-突触核蛋白（α-syn）预制纤维（PFF）。表观基因组是一个潜在的调解人 发育暴露、神经元脆弱性增加和成人疾病之间的关系。一致 有了这个想法，我们最近确定了性别特异性差异甲基化模式， 狄氏剂暴露。我们假设狄氏醇诱导的表观遗传修饰在发育过程中 导致基因表达和表型的变化，持续到成年期，改变敏感性， 对帕金森病的侮辱和促进发展的PD。 为了验证这一假设，我们将确定细胞类型特异性DNA修饰和表达谱， 先前在狄氏剂模型中确定的候选基因（Aim 1）;分析突触末梢在 我们新的狄氏剂/PFF两次打击模型（目的2）;并确定是否狄氏剂或候选基因的表达改变 影响多巴胺能神经元细胞培养模型中对α-syn PFF的易感性（目的3）。远景目标 这些实验的目的是确定狄氏醇相关的差异甲基化基因是否在 在对帕金森病毒性的生物反应中的功能作用。 这些目标的完成将进一步推动NIEHS的使命，以增加我们对环境如何影响的理解。 影响人们，以促进更健康的生活，具体的项目目标是将暴露与 基因表达、神经元表型和PD易感性的功能变化。提出的实验 这将有助于建立一个生物学机制，将发育暴露与晚年疾病联系起来。这个项目 通过建立一个新的基因组，我们还将扩大我们的工具库，以询问表观遗传变化的功能。 体外实验范例连接特定的表观遗传机制与帕金森病毒性。随着我们在 结合发育暴露与成人PFF注射的体内模型，我们将有一组实验性的 系统到位，将允许我们测试各种各样的曝光，以及曝光的组合， 无论是在体内还是体外。总之，这套工具将使我们能够探索PD- 相关暴露改变了PD中神经元的脆弱性，进一步推动了NIEHS的目标，以了解如何结合 接触会影响疾病的发病机理和个人的易感性。