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，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，并将这两个发现联系起来，以告知金属和污染物引起CVD的潜在生物途径。我们对这些机制的理解目前是初步的，并且通常基于动物的高剂量。甲基组学提供了一个有前途的方法来识别重要的途径，在人类的利益暴露范围。这项工作的意义在于开发基因组生物标志物，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或其根本原因而导致的基因组甲基化变化的新方法。CVD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。我们的方法利用了一个纵向队列，跟踪了超过48年，具有丰富的DNA档案和数据库，其中包含广泛的CVD表型和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.