Environmental exposure, DNA methylation, and Parkinson's disease

环境暴露、DNA 甲基化和帕金森病

• 批准号: 8758444
• 负责人: Steve Horvath
• 金额: $ 23.1万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-06 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8758444
• 关键词: Acceleration; Address; Affect; Age; Agriculture; Bioinformatics; Biological; Biological Markers; Biometry; Blood; Brain; California; Case-Control Studies; Chronic; Clinical; Coffee; Cognitive; Consumption; DNA; DNA Methylation; Data; Defect; Development; Diagnosis; Disease; Disease Progression; Dose; Elderly; Enrollment; Environment; Environmental Exposure; Environmental Health; Environmental Risk Factor; Epidemiology; Epigenetic Process; Genes; Genetic; Genetic Markers; Genetic Variation; Genome; Geographic Information Systems; Health; Human; Human Genetics; Interdisciplinary Study; Investigation; Left; Link; Literature; Location; Maps; Measures; Mental Depression; Methodology; Methods; Methylation; Motor; Movement Disorders; Neurodegenerative Disorders; Neurons; Neurosciences; Neurotoxins; Onset of illness; Parkinson Disease; Participant; Patients; Pattern; Pesticides; Pilot Projects; Play; Positioning Attribute; Predisposition; Prevention; Process; Public Policy; Regulation; Regulator Genes; Resolution; Risk Factors; Role; Sample Size; Site; Smoking; Specialist; Stress; Systems Biology; Technology; Testing; Time; Tissues; Toxic Environmental Substances; Toxicant exposure; age related; alpha synuclein; base; case control; cell type; cohort; cost; disorder risk; epigenetic marker; epigenome; epigenomics; experience; functional decline; gene interaction; genome-wide; improved; land use; meetings; neurotoxic; non-motor symptom; novel strategies; pesticide exposure; population based; promoter; public health relevance; response; success; therapeutic development; tool

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.

描述（由申请人提供）：PEG研究提供了有关人类帕金森病（PD）中农药和农药-基因相互作用的重要且开创性的结果，现在提供了独特的机会来扩展其识别暴露和疾病的表观遗传特征的目标在PD。许多农药接触是低剂量的、慢性的或间歇性的，并且是在其他接触和影响帕金森病易感性的风险因素的背景下发生的。当疾病发生时，大多数这些接触物（那些没有在体内长期储存的物质）无法用现有的生物标志物检测到，尽管它们可能对神经元和大脑造成损害并改变了许多细胞类型和组织的表观基因组。我们将其称为留下由暴露引起的“生物特征”，我们假设在诊断疾病时该“生物特征”仍然存在。在这里，我们建议使用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有毒暴露的特征。尽管 DNA 甲基化可以说是最容易理解和研究最广泛的表观遗传机制，但我们对哪些特定表观遗传标记 (CpG) 与有毒物质暴露相关以及这些表观遗传变化在 PD 中发挥的作用知之甚少。虽然老年人神经退行性疾病的生物标志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，有望促进对与破坏的基因调控过程相关的环境压力因素进行更全面的评估。该提案使用最新版本的经过充分验证的 Ilumina Infinium DNA 甲基化阵列，将生成高分辨率的全基因组 DNA 甲基化图谱，然后使用最先进的统计方法将其与现有的临床、遗传和生物标志物数据集成。该试点研究相对较大的样本量（720 名受试者）提供了足够的统计能力来探索 与暴露相关的表观基因组变化在帕金森病中的作用，并探讨当前和/或持续的环境暴露（即疾病发作后发生的环境暴露）是否以及如何改变帕金森病的轨迹。 PEG研究具有独特的定位，可以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志物来预测疾病的发作和进展。这两位 PI 拥有广泛的专业知识，在流行病学、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进行跨学科研究。这些专业知识和经验是成功执行假设驱动和假设生成研究的必要先决条件，该研究将 Illumina DNA 甲基化技术应用于现有生物样本，以研究环境暴露对帕金森病表观遗传决定因素的影响。