DNA Methylation as a Biomarker of Exposure and Effect for Particles and Metals

描述（由申请人提供）：我们建议更新我们正在进行的环境表观遗传学研究，并扩大工作范围以发现和验证空气污染物和有毒金属暴露的生物标志物。我们还建议开发 CVD 本身的表观基因组生物标志物，并将这两个发现联系起来，以了解金属和污染物引起 CVD 的潜在生物途径。目前我们对这些机制的了解还很初级，并且通常基于动物的高剂量。甲基组学提供了一种有前途的方法来识别人类在感兴趣的暴露范围内的重要途径。这项工作的意义在于基因组生物标志物的开发，这是一种利用 DNA 甲基化的独特特性和高度发达的技术来测量由于 CVD 或其根本原因导致的整个基因组甲基组变化的新方法。迫切需要 CVD 及其风险因素（例如空气污染和金属）的生物标记物，特别是考虑到美国人口老龄化，此类标记物可以帮助早期诊断和预防疾病进展。我们经验丰富的研究团队包括流行病学、表观遗传学、毒理学、金属分析、生物信息学、统计学和暴露生物学方面的专业知识。我们拥有独特的优势，可以利用最近开发的表观基因组平台，在 CVD 环境原因的创新纵向研究中发现暴露的验证生物标志物。我们的方法利用了追踪超过 48 年的纵向队列，拥有丰富的 DNA 档案和包含广泛的 CVD 表型分析和空气污染物和有毒金属暴露的纵向测量的数据库。 公共卫生相关性：该项目与公共卫生研究相关，因为它将识别基因特异性甲基化的变化，这些变化可用作使用易于获取的组织（血液）暴露的内部生物标志物。同时，它将在易于接近的组织中识别 DNA 甲基化的基因特异性模式，这些模式先于心血管中介物（血压、炎症标志物等）的变化，并先于心血管事件和死亡的发生。

DESCRIPTION (provided by applicant): We are proposing to renew our ongoing research in Environmental Epigenetics and expand the work to discover and validate biomarkers of exposure to air pollutants and toxic metals. We also propose to develop epigenomic biomarkers of CVD itself and to link these two findings to inform potential biological pathways via which metals and pollutants cause CVD. Our understanding of these mechanisms is currently rudimentary, and often based on high doses in animals. Methylomics offers a promising approach to identification of important pathways in humans at the exposure ranges of interest. The significance of this work lies in the development of genomic biomarkers, a novel approach which utilizes the distinct properties of DNA methylation and the highly developed technologies to measure methylomic changes across the genome due to either CVD or its root causes. Biomarkers of CVD and its risk factors such as air pollution and metals are badly needed, particularly given the aging of the US population, such markers can aid in early diagnosis and prevention of disease progression. Our experienced team of investigators includes expertise in epidemiology, epigenetics, toxicology, metals analysis, bioinformatics, statistics and exposure biology. We are uniquely positioned to use recently developed epigenomic platforms to discover the validate biomarkers of exposure in an innovative longitudinal study of environmental causes of CVD. Our approach utilizes a longitudinal cohort followed for over 48 years, with a rich archive of DNA and a database with extensive CVD phenotyping and longitudinal measures of exposure to air pollutants and toxic metals. PUBLIC HEALTH RELEVANCE: This project is relevant for public health research because it will identify changes in gene specific methylation that can be used as internal biomarkers of exposure using easily accessible tissue (blood). Simultaneously, it will identify gene specific patterns of DNA methylation in easily accessible tissue that precede changes in cardiovascular intermediaries (blood pressure, inflammatory markers, etc) and precede the incidence of cardiovascular events and deaths.