Epigenomic Mechanism of Parkinson's Disease

帕金森病的表观基因组机制

基本信息

批准号：
8738730
负责人：
Xiongwei Zhu
金额：
$ 19.99万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-20 至 2016-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8738730
关键词：
1-Methyl-4-phenylpyridinium Affect Age Aging Autopsy Brain Cells Cytokine Gene DNA Methylation Data Disease Disease Progression Environmental Risk Factor Epigenetic Process Future Gene Expression Genes Genetic Genetic Determinism Human Levodopa Lewy Bodies Mediator of activation protein Methods Methylation Molecular Movement Movement Disorders Mus Nerve Degeneration Neurodegenerative Disorders Neurons Neurotoxins Parkinson Disease Parkinsonian Disorders Pathogenesis Pathway interactions Patients Pattern Pesticides Play Reagent Regulation Research Personnel Risk Factors Role Series Signal Pathway Signal Transduction Site Substantia nigra structure Techniques Testing Toxic Environmental Substances Tremor adult neurogenesis age related base brain tissue dopaminergic neuron dosage epigenomics genome-wide insight mind control mouse model neurogenesis novel pars compacta prevent public health relevance therapeutic development

项目摘要

DESCRIPTION (provided by applicant): Compelling evidence suggests that both genetic factors and environmental factors play important roles in the pathogenesis of PD. Over 13 genetic loci have been identified in the familial forms of PD. Aging and a number of neurotoxins, including MPTP and certain pesticides, are known risk factors of human parkinsonia. However, the underlying molecular mechanism of the disease-associated environmental factors, particularly, their interaction with genetic factors in PD pathogenesis, remains poorly understood. It is thought that epigenetic changes are mediators between genetic determinants and aging or environmental toxins. In a preliminary study, we determined the global methylation status of 80,000-110,000 highly informative CpG sites in brain tissue from a series of sporadic PD patient and well-matched control patients utilizing novel sequencing technique and we found that multiple genes involved in neurogenesis, particularly the ones in the wnt signaling pathway, were hypermethylated in PD brains. Consistent with this notion, genome-wide expression analysis of SH-SY5Y cells treated with sub-lethal dosage of MPP+ revealed reduced expression of genes in wnt pathways along with increased expression of cytokine genes. These findings demonstrate that specific functional pathways, such as the wnt pathway, are epigenetically dysregulated during the pathogenesis and progression of PD. Our preliminary results support an important role of epigenetic regulation in PD pathogenesis. Based on these exciting preliminary data, we hypothesize that environmental risk factors contribute significantly to initiation and progression of PD via, at least partially, an epigenetic- involved mechanism. In this study, we propose to determine the functional pathways dysregulated by DNA methylation in PD patient brains. We will also determine whether known environmental toxins induce similar changes of DNA methylation in mouse models. Finally, we will select the wnt pathway as a target to determine the role of its dysregulation in the pathogenesis of PD as proof of concept. Successful completion of the study will provide novel insights into the mechanisms through which environmental factors contribute to PD pathogenesis and identify genes or pathways as potential targets for future development of therapeutic reagents.

描述（由申请人提供）：令人信服的证据表明遗传因素和环境因素在帕金森病的发病机制中发挥着重要作用。在帕金森病的家族性形式中，已鉴定出超过 13 个遗传位点。衰老和许多神经毒素，包括 MPTP 和某些杀虫剂，是人类帕金森病的已知危险因素。然而，与疾病相关的环境因素的潜在分子机制，特别是它们在帕金森病发病机制中与遗传因素的相互作用，仍然知之甚少。人们认为表观遗传变化是遗传决定因素与衰老或环境毒素之间的中介因素。在一项初步研究中，我们利用新型测序技术确定了一系列散发性 PD 患者和匹配良好的对照患者脑组织中 80,000-110,000 个信息丰富的 CpG 位点的整体甲基化状态，我们发现多个基因参与神经发生，特别是wnt 信号通路中的那些在 PD 大脑中高度甲基化。与这一观点一致的是，用亚致死剂量的 MPP+ 处理的 SH-SY5Y 细胞的全基因组表达分析显示，wnt 通路中基因的表达减少，同时细胞因子基因的表达增加。这些发现表明，特定的功能通路（例如 wnt 通路）在 PD 的发病机制和进展过程中出现表观遗传失调。我们的初步结果支持表观遗传调控在帕金森病发病机制中的重要作用。基于这些令人兴奋的初步数据，我们假设环境风险因素至少部分通过表观遗传相关机制对帕金森病的发生和进展产生显着影响。在这项研究中，我们打算确定 PD 患者大脑中 DNA 甲基化失调的功能途径。我们还将确定已知的环境毒素是否会在小鼠模型中引起类似的 DNA 甲基化变化。最后，我们将选择wnt通路作为靶点来确定其失调在PD发病机制中的作用作为概念证明。该研究的成功完成将为了解环境因素导致帕金森病发病机制提供新的见解，并确定基因或途径作为未来治疗试剂开发的潜在目标。