Environmental exposure, DNA methylation, and Parkinson's disease

描述(申请人提供)：聚乙二醇酯研究在人类帕金森氏病(PD)的农药和农药-基因相互作用方面提供了重要和开创性的结果，现在提供了独特的机会来扩大其目标，以确定帕金森病暴露和疾病的表观遗传特征。许多农药暴露是低剂量、慢性或间歇性的，发生在影响帕金森病易感性的其他暴露和危险因素的背景下。到疾病发生时，大多数接触到的物质--那些在体内没有长期储存的物质--无法用现有的生物标志物检测到，即使它们可能对神经元和大脑造成了损害，并改变了许多细胞类型和组织的表观基因组。我们指的是留下一个由暴露引起的‘生物学特征’，当疾病被诊断出来时，我们假设它仍然存在。在这里，我们建议使用一种强大的新工具和系统生物学分析方法来识别引起长期生物反应的毒性暴露的特征。虽然DNA甲基化可以说是最被理解和最广泛研究的表观遗传学机制，但对于哪些特定的表观遗传学标记物(CPGs)与中毒暴露相关，以及这些表观遗传学变化在帕金森病中所起的作用，人们知之甚少。虽然老年人神经退行性疾病的生物标记物研究取得了一些成功，但表观基因组技术的发展与整合这些数据的分析工具相结合，有望促进对与扰乱基因调控过程相关的环境应激因素进行更全面的评估。使用经过充分验证的最新版本的ILumina Infinium DNA甲基化阵列，这项建议将生成高分辨率全基因组DNA甲基化图谱，然后将其与现有的临床、遗传和生物标记物数据结合使用最先进的统计方法。这项初步研究的样本量相对较大(720名受试者)，这为探索 与暴露相关的表观基因组变化在帕金森病中的作用，并探索当前和/或持续的环境暴露(即，那些发生在疾病发病后的暴露)是否以及如何改变帕金森病的发病轨迹。这项聚乙二醇研究的独特之处在于研究慢性环境应激因素是否影响表观基因组，以及是否可以在老年人和帕金森病患者中找到临床上有用的生物标记物来预测疾病的发生和发展。这两个私人投资机构拥有广泛的专业知识，开展跨学科研究，涉及流行病学、环境健康、人类遗传学、生物信息学、生物统计学和神经科学等领域。这种专业知识和经验是成功进行假说驱动和假说生成研究的必要前提，该研究将Illumina DNA甲基化技术应用于现有的生物标本，以调查环境暴露对帕金森病表观遗传决定因素的影响。

DESCRIPTION (provided by applicant): The PEG study has provided important and groundbreaking results on pesticide and pesticide-gene interactions in Parkinson's disease (PD) in humans, and now offers the unique opportunity to extent its aims to identify epigenetic signatures of exposure and disease in PD. Many pesticide exposures are low dose and chronic or episodic and occur on a background of other exposures and risk factors that affect the susceptibility to PD. By the time disease occurs, most of these exposures - those agents without long-term storage in the body - are not detectable with existing biomarkers even though they may have caused damage to neurons and brain and altered the epigenome of many cell types and tissues. We refer to this as leaving a 'biological signature' evoked by exposures which we hypothesize to still be present when disease is diagnosed. Here we propose to use a powerful new tool and systems biology analytic methods to identify signatures for toxic exposures that evoke long-term biologic responses. Although DNA methylation is arguably the best understood and most widely studied epigenetic mechanism, little is known about which specific epigenetic markers (CpGs) correlate with toxic exposures and what role these epigenetic changes play in PD. While biomarker studies of neurodegenerative diseases in the elderly have met with some success, the development of epigenome wide technologies combined with analytic tools to integrate these data promises to facilitate a more comprehensive assessment of environmental stress factors tied to disrupted gene regulatory processes. Using the latest version of the well-validated Ilumina Infinium DNA methylation array, this proposal will generate high-resolution genome wide DNA methylation profiles which will then be integrated with existing clinical, genetic, and biomarker data using state of the art statistical methodologies. The relatively large sample size (720 subjects) of this pilot study provides sufficient statistical power to explore the role of exposure-related epigenomic changes in PD and to explore whether and how current and/or ongoing environmental exposures (i.e., those occurring after the onset of disease) alter PD disease trajectory. The PEG study is uniquely positioned to study whether chronic environmental stress factors influence epigenome and whether clinically useful biomarkers in the elderly and PD patients can be found that predict disease onset and progression. The two PIs have broad expertise conducting interdisciplinary research spanning the fields of epidemiology, environmental health, human genetics, bioinformatics, biostatistics, and neuroscience. This expertise and experience is a necessary prerequisite for the successful execution of both a hypothesis driven and hypothesis generating investigation that applies Illumina DNA methylation technology on existing biospecimens to investigate the effect of environmental exposures on epigenetic determinants of Parkinson's disease.