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

描述（由申请人提供）：我们提议更新我们正在进行的环境表观遗传学研究，并扩大工作，以发现和验证暴露于空气污染物和有毒金属的生物标志物。我们还建议开发CVD本身的表观基因组生物标志物，并将这两项发现联系起来，以了解金属和污染物导致CVD的潜在生物学途径。我们对这些机制的理解目前还很初级，而且通常是基于对动物的高剂量试验。甲基组学提供了一种很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发展，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心血管疾病或其根本原因导致的基因组甲基化变化的新方法。心血管疾病及其危险因素（如空气污染和金属）的生物标志物是迫切需要的，特别是考虑到美国人口的老龄化，这些标志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。我们具有独特的优势，可以使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有效生物标志物。我们的方法利用纵向队列跟踪超过48年，具有丰富的DNA档案和广泛的CVD表型数据库，以及暴露于空气污染物和有毒金属的纵向测量。

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.