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

描述(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，并扩大发现和验证暴露于空气污染物和有毒金属的生物标记物的工作。我们还建议开发CVD本身的表观基因组生物标记物，并将这两个发现联系起来，以揭示金属和污染物引起CVD的潜在生物学途径。我们对这些机制的了解目前还很初级，而且往往是基于动物的高剂量。甲基组学为在感兴趣的暴露范围内确定人类的重要途径提供了一种很有前途的方法。这项工作的意义在于开发基因组生物标记物，这是一种利用DNA甲基化的独特性质和高度发达的技术来测量由于心血管疾病或其根本原因而引起的整个基因组的甲基组变化的新方法。心血管疾病及其风险因素(如空气污染和金属)的生物标记物是迫切需要的，特别是考虑到美国人口老龄化，这些标记物可以帮助早期诊断和防止疾病进展。我们经验丰富的调查团队包括流行病学、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。我们处于独特的地位，可以使用最近开发的表观基因组学平台，在一项关于心血管疾病环境原因的创新纵向研究中发现暴露的验证生物标记物。我们的方法利用了跟踪超过48年的纵向队列，拥有丰富的DNA档案和数据库，具有广泛的CVD表型和暴露于空气污染物和有毒金属的纵向测量。 公共卫生相关性：该项目与公共卫生研究相关，因为它将确定基因特异性甲基化的变化，这些变化可用作使用容易获得的组织(血液)暴露的内部生物标记物。同时，它将在容易接触的组织中识别DNA甲基化的基因特异性模式，这些模式先于心血管媒介(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.