The Toxic Environment and the Epigenetics of Fetal Growth

描述（由申请人提供）：K23指导的以患者为导向的研究职业发展奖的申请包括一个为期5年的培训和研究活动计划，该计划将提供作为独立研究者取得成功所需的技能和经验，研究环境和表观遗传机制在出生结果中的作用。候选人已经完成了研究和临床奖学金，为她的学术生涯做好了准备，研究围产期社会流行病学，目前是贝斯以色列女执事医疗中心新生儿科的全职教员。候选人是哈佛医学院新生儿医学部的核心成员，担任儿科讲师，这是哈佛的标准入门级学术职位。这项K23奖将为她提供必要的结构和支持，以实现以下目标：（1）评估砷在胎儿生长中的作用;（2）评估砷在与胎儿生长有关的基因（如炎症细胞因子基因和糖皮质激素受体基因）的DNA甲基化中的作用，并探索砷是否通过这种表观遗传机制影响胎儿生长;（3）获得环境毒理学和环境表观遗传学分析方面的专业知识;（4）学习管理大型队列研究所需的管理技能，以便完成向独立研究职业的过渡。候选人的目标是研究有毒化学环境在美国出生结果差异中的作用。为了实现这些目标，Burris博士组建了一个由主要导师Robert Wright，MD MPH，儿科和环境健康副教授组成的指导团队，他是儿科环境健康和毒理学专家，以及共同导师Andrea Baccarelli，MD PhD，Mark和Catherine Winkler环境表观遗传学副教授，他在表观遗传分析方面具有专业知识。虽然已知砷等化学物质会影响出生结果，并已知会影响DNA甲基化，但DNA甲基化是否介导砷与出生体重的关联仍不清楚。这项研究旨在验证砷损害胎儿生长的假设，即砷导致炎症细胞因子基因和糖皮质激素受体基因的DNA甲基化改变。候选人将探讨DNA甲基化紊乱是否介导砷-出生体重的关联。这些分析将在Wright博士指导的墨西哥城（ELEMENT）先前建立的、目前资助的队列中进行。候选人将利用贝斯以色列女执事医疗中心，哈佛催化剂（临床和转化科学中心）和公共卫生的哈佛学校提供的丰富资源，以获得必要的培训和课程，以补充通过这些分析获得的实践培训，成为一名独立的调查员，研究环境对出生结果差异的影响。

DESCRIPTION (provided by applicant): This application for a K23 Mentored Patient-Oriented Research Career Development Award includes a 5-year plan for training and research activities that will provide the skills and experience needed to achieve success as an independent investigator studying the role of the environment and epigenetic mechanisms in birth outcomes. The candidate has completed research and clinical fellowships that prepared her for an academic career studying perinatal social epidemiology and is currently a full-time faculty member in the Department of Neonatology at Beth Israel Deaconess Medical Center. The candidate is a core member of the Division of Newborn Medicine at Harvard Medical School serving as an Instructor in pediatrics, which is the standard entry level academic position at Harvard. This K23 award will provide her with the structure and support necessary to accomplish the following goals: (1) assess the role that arsenic plays in fetal growth; (2) assess the role arsenic plays in the DNA methylation of genes involved in fetal growth such as inflammatory cytokine genes and the glucocorticoid receptor gene, and explore whether arsenic affects fetal growth through such epigenetic mechanisms; (3) gain expertise in environmental toxicology and environmental epigenetic analyses; and (4) learn the administrative skills needed to manage a large cohort study so that transition to an independent research career running her own birth cohort is accomplished. The candidate's goal is to examine the role the toxic chemical environment plays in birth outcome disparities in the US. To achieve these goals, Dr. Burris has assembled a mentoring team comprised of a primary mentor, Robert Wright, MD MPH, Associate Professor of Pediatrics and Environmental Health who is an expert in pediatric environmental health and toxicology, and co-mentor Andrea Baccarelli, MD PhD, the Mark and Catherine Winkler Associate Professor of Environmental Epigenetics, who has expertise in epigenetic analyses. Although chemicals like arsenic are known to affect birth outcomes and known to affect DNA methylation, it remains unknown whether DNA methylation mediates arsenic-birth weight associations. The study proposed is designed to test the hypothesis that arsenic impairs fetal growth, that arsenic causes alterations in the DNA methylation of inflammatory cytokine genes and the glucocorticoid receptor gene. The candidate will explore whether DNA methylation disturbances mediate arsenic-birth weight associations. These analyses will be performed within a previously established, currently funded cohort in Mexico City (ELEMENT) directed by Dr. Wright. The candidate will use the abundant resources available at Beth Israel Deaconess Medical Center, the Harvard Catalyst (Clinical and Translational Science Center) and the Harvard School of Public Health to obtain the training and coursework necessary to supplement the practical training attained through these analyses to become an independent investigator with a research program studying the environmental impact on birth outcome disparities.