Intrauterine Metal Exposure, Placental Gene Networks and Fetal Growth

项目摘要 在子宫内期间的扰动，包括暴露于有毒水平的微量金属，可能会破坏 适当的胎儿生长和发育，并对整个生命周期的健康产生不利影响。 单独的.胎盘是解释来自子宫内环境的线索以告知 然而，胎盘转录组活性的变化尚未被系统地评价为一种 胎儿生长异常的可能介质。全面评估下列方面之间的相互关系： 金属混合物暴露，胎盘基因活性和胎儿生长是可行的， 然而，高维暴露和基因组数据的可用性，充分利用生物学的潜力， 这些大规模数据集中保留的信息还有待实现。 为了解决这些现有的差距，我们概述了研究和培训的目的，以进行环境混合 在高通量基因组学数据的背景下，在基于人群的研究中建模，并在 生物系统。这项研究首次全面整合了多金属暴露 和胎盘基因组学数据在流行病学环境中。我们将利用现有资源进行这项研究 在RICHS，一个正在进行的，以前资助的队列，使我们能够识别新的环境敏感的 生物标志物的成本效益。通过拟议的研究获得的知识和开发的工具 可以应用于其他环境，并有可能更广泛地了解子宫内的影响， 环境对健康的影响贯穿整个生命周期。 为了进行拟议的研究，我将接受高级生物统计学、系统生物学和分子生物学的培训 方法，因为我通过研究目标的进展与不断反馈，从我的顾问团队在整个过程中 我们定期安排的会议。通过正式的课程和贾博士提供的指导。 陈，克里斯·詹宁斯，卡门·马西特，柯浩和钱璐，我将获得知识和培训 有必要发展成为一个独立的，跨学科的研究人员，重点是阐明 将宫内环境暴露与不良出生结果联系起来的分子机制。

PROJECT SUMMARY Perturbations during the intrauterine period, including exposures to toxic levels of trace metals, may disrupt appropriate fetal growth and development and adversely impact health throughout the lifespan of the individual. The placenta is the principal organ interpreting cues from the intrauterine environment to inform fetal development, yet, changes in placental transcriptomic activity has not been systematically evaluated as a possible mediator of fetal growth abnormalities. Comprehensively assessing the interrelationship between metal mixture exposure, placental gene activity and fetal growth is becoming feasible with the increasing availability of high-dimensional exposure and genomic data, however, the potential to fully harness the biologic information retained in these large scale data-sets has yet to be realized. To address these existing gaps, we outlined research and training aims to conduct environmental mixture modeling in a population-based study in the context of high-throughput genomics data with verification in a biological system. The proposed study represents the first comprehensive integration of multi-metal exposure and placental genomics data in an epidemiologic setting. We will conduct this study using available resources in RICHS, an ongoing, previously funded cohort, enabling us to identify novel environmentally sensitive biomarkers in a cost-effective manner. The knowledge gained and tools developed through the proposed study may be applied in other settings and have the potential to inform more broadly on the influence of the in utero environment on health throughout the lifespan. To conduct the proposed study, I will train in advanced biostatistics, systems biology and molecular biology methods as I progress through the research aims with continual feedback from my advisory team throughout our regularly scheduled meetings. Through formal coursework and the mentored guidance provided by Drs. Jia Chen, Chris Gennings, Carmen Marsit, Ke Hao and Qian Lu, I will obtain the knowledge and training necessary to develop into an independent, interdisciplinary researcher with a focus on elucidating the molecular mechanism linking in utero environmental exposures to adverse birth outcomes.