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研究提供了关于人类帕金森病（PD）中农药和农药-基因相互作用的重要和开创性结果，现在提供了独特的机会，以扩大其识别PD暴露和疾病的表观遗传特征的目标。许多农药暴露是低剂量和慢性或偶发性的，并且发生在影响PD易感性的其他暴露和风险因素的背景下。当疾病发生时，这些暴露中的大多数-那些在体内没有长期储存的药剂-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损伤，并改变了许多细胞类型和组织的表观基因组。我们称之为留下由暴露引起的“生物特征”，我们假设当疾病被诊断时仍然存在。在这里，我们建议使用一个强大的新工具和系统生物学分析方法，以确定引起长期生物反应的有毒暴露的签名。尽管DNA甲基化可以说是最好理解和最广泛研究的表观遗传机制，但对于哪些特定的表观遗传标记（CpG）与毒性暴露相关以及这些表观遗传变化在PD中起什么作用知之甚少。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分析工具相结合，整合这些数据，有望促进对与基因调控过程中断相关的环境压力因素进行更全面的评估。使用最新版本的经过充分验证的Ilumina Infinium DNA甲基化阵列，该提案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整合。这项初步研究的相对较大的样本量（720名受试者）提供了足够的统计效力来探索 PD中与糖尿病相关的表观基因组变化的作用，并探索当前和/或正在进行的环境暴露（即，在疾病发作后发生的那些）改变PD疾病轨迹。PEG研究独特地定位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PD患者中发现预测疾病发作和进展的临床有用的生物标志物。这两个PI具有广泛的专业知识，进行跨学科研究，涵盖流行病学，环境健康，人类遗传学，生物信息学，生物统计学和神经科学领域。这种专业知识和经验是成功执行假设驱动和假设生成调查的必要前提，该调查将Illumina DNA甲基化技术应用于现有生物标本，以调查环境暴露对帕金森病表观遗传决定因素的影响。