Prenatal air pollution, DNA methylation and early signs of atherosclerosis

描述（由申请人提供） 博士卡丽布雷东获得了理学博士学位。她于2007年从哈佛公共卫生学院获得流行病学博士学位，目前是南加州大学预防医学系的助理教授，她是由Frank Gilliland博士领导的高度互动的环境健康小组的一员。拟议的五年职业发展奖的目标是为布雷东博士提供成为独立研究人员所需的知识和必要技能。包括研究项目，诊所和实验室轮换，非正式和结构化的课程，研讨会和指导的综合方法旨在实现以下具体目标：1）建立临床心血管流行病学的综合知识库，重点关注儿童可能存在的心血管疾病标志物，掌握正确分析和综合表观遗传数据所需的新兴统计/生物信息学技术。三位高素质和经验丰富的导师将监督她的培训。Gilliland博士（环境流行病学）将担任主要导师，而霍华德霍迪斯博士（动脉粥样硬化研究单位）和Kim Siegmund博士（表观遗传学生物信息学）将分别担任共同导师。科学文化和合作研究的气氛都在部门和大学提供了一个理想的环境，为候选人的学术生涯发展。布雷东博士的研究项目的目的是了解产前颗粒物和交通暴露，动脉粥样硬化和新生儿血液中DNA甲基化的作用之间的关系。具体而言，该项目追求的假设是：1）产前暴露于PM2.5和交通相关污染物促进动脉粥样硬化形成，这些暴露的差异导致儿童颈动脉厚度（IMT）和硬度的差异; 2）产前空气污染暴露对IMT/僵硬的影响是通过DNA甲基化的差异介导的，因此，新生儿血液中重复元件和单个CpG位点的DNA甲基化水平与儿童IMT/僵硬相关，产前暴露于空气污染会改变这些DNA甲基化水平。这些假设将使用儿童健康研究的一个子集中提供的大量健康和暴露数据进行研究，该研究是一项正在进行的队列研究，涉及11，000名儿童，调查与呼吸道疾病相关的遗传和环境因素。这项研究的独特之处在于，它整合了一项基于儿童人群的大型研究、尖端的表观基因组资源、使用干燥的新生儿血斑以及一个广泛的空气污染监测网络，其中包括从出生开始的暴露信息。这项研究的结果将有助于通过调查空气污染物，DNA甲基化和早期生命动脉粥样硬化之间的新关联来快速发展的环境表观基因组学领域。此外，年轻时IMT和僵硬度的微小差异可能在以后的生活中转化为临床相关的心血管疾病-美国发病率和死亡率的主要原因。

DESCRIPTION (provided by applicant) Dr. Carrie Breton received her Sc.D. in epidemiology in 2007 from the Harvard School of Public Health and is currently an Assistant Professor in the Department of Preventive Medicine at the University of Southern California where she is part of a highly interactive environmental health group headed by Dr. Frank Gilliland. The goal of the proposed five-year career development award is to provide Dr. Breton with the knowledge and necessary skills to become an independent researcher. A integrated approach comprised of a research project, clinic and laboratory rotations, informal and structured coursework, seminars, and mentoring has been designed to accomplish the following specific goals: 1) develop a comprehensive knowledge base in clinical cardiovascular epidemiology, with a focus on markers of cardiovascular disease that may be present in children, and 2) master the emerging statistical/bioinformatics techniques necessary for properly analyzing and synthesizing epigenetic data. Three highly qualified and experienced mentors will supervise her training. Dr. Gilliland (environmental epidemiology) will serve as the primary mentor, while Drs. Howard Hodis (Atherosclerosis Research Unit) and Kim Siegmund (bioinformatics for epigenetics) will serve as respective co- mentors. The scientific culture and collaborative research atmosphere both in the Department and in the University provide an ideal environment for the candidate's academic career development. The objective of Dr. Breton's research project is to understand the relationship between prenatal particulate matter and traffic exposures, atherosclerosis and the role of DNA methylation in newborn blood. Specifically, the project pursues the hypotheses that 1) prenatal exposures to PM2.5 and traffic-related pollutants promote atherogenesis, and that differences in these exposures lead to differences in carotid artery thickness (IMT) and stiffness measured in children; 2) the effects of prenatal air pollution exposures on IMT/stiffness are mediated through differences in DNA methylation, such that levels of DNA methylation in repetitive elements and in individual CpG loci in newborn blood are associated with IMT/stiffness in children and prenatal exposure to air pollution alters these levels of DNA methylation. These hypotheses will be investigated using the wealth of health and exposure data available in a subset of the Children's Health Study, an ongoing cohort study of 11,000 children investigating both genetic and environmental factors related to respiratory disease. The unique feature of the proposed study is the integration of a large children's population-based study, cutting edge epigenomic resources, use of dried newborn blood spots, and an extensive air pollution monitoring network with exposure information from birth forward. The results from this research will contribute to the rapidly evolving field of environmental epigenomics by investigating novel associations between air pollutants, DNA methylation, and early life atherogenesis. Moreover, small differences in IMT and stiffness at a young age may translate into clinically relevant cardiovascular disease later in life - a leading cause of morbidity and mortality in the U.S.