The Role of Aquaporin 3 in Arsenic-Induced DNA Damage and Mutagenesis

项目摘要 砷是一种广泛存在于饮用水中的毒素，影响着数百万人， 神经退行性疾病和心血管疾病以及癌症。高剂量的砷会导致DNA损伤， 基因组不稳定性然而，与低剂量砷相关的健康影响是有争议的。最近， 我们发现DNA损伤组蛋白（DDP）的大网络促进DNA损伤和基因组 不稳定性（Xia et al. Cell 2019）。我们还发现水通道蛋白3（AQP 3）是一种新的肺癌相关DDP。 本申请描述了AQP 3与低剂量砷相互作用以促进DNA 损伤，绘制AQP 3的方法，砷诱导的双链断裂（DSB）热点，以及相关的 人类细胞和群体中的突变特征。具体而言，它将（1）提供机械的见解， AQP 3如何增强砷诱导的DNA损伤，（2）绘制AQP 3和低剂量砷引起的DSB 相互作用，和（3）确定AQP 3和砷诱导的基因组不稳定性和突变特征。的 提出的研究将使内源性DNA损伤和DNA损伤蛋白质的功能， 与环境毒物相互作用。低剂量砷如何与风险相互作用的机制见解 基因是预防、诊断和治疗砷相关疾病的关键知识。这 该项目将确定早期生物标志物，以预测砷对健康的长期影响，并揭示突变 特征来推断癌症病因并揭示过去的砷暴露。最后，在此基础上开发的平台 这一建议将有助于揭示环境毒物和/或致癌物对宿主的影响 基因.除了其科学的建议，这个应用程序还列出了一个全面的培训计划， 帮助候选人实现他的职业目标，成为一名独立的调查员， 内源性DNA损伤的背景，以更好地了解基因-外源性环境因子（例如， 砷）相互作用。在环境健康，正式的生物信息学， 定量基因组学培训，以及CRISPR和类器官培训将使他处于一个独特的位置， 解决具有挑战性的环境健康研究问题。Chris Amos博士，临床研究所所长 贝勒医学院的转化研究将领导一个由共同导师和顾问组成的小组， 委员会成员就研究和职业发展提供建议，并晋升为终身职位 跟踪位置。

PROJECT SUMMARY Arsenic is a widespread toxin in drinking water that affects millions of people, increasing the risks of neurodegenerative and cardiovascular diseases and cancers. High doses of arsenic cause DNA damage and genome instability. However, the health effects associated with low-dose arsenic are controversial. Recently, we discovered that large networks of DNA damageome proteins (DDPs) promote DNA damage and genome instability (Xia et al. Cell 2019). We also found that Aquaporin 3 (AQP3) is a new lung cancer-associated DDP. This application describes the mechanism by which AQP3 interacts with low-dose arsenic to promote DNA damage, an approach to map AQP3, arsenic-induced double-strand break (DSB) hotspots, and associated mutation signatures in human cells and populations. Specifically, it will (1) provide mechanistic insights into how AQP3 potentiates arsenic-induced DNA Damage, (2) map DSBs caused by AQP3 and low-dose arsenic interactions, and (3) identify AQP3 and arsenic-induced genome instability and mutational signatures. The proposed studies will bring function to endogenous DNA damage and the DNA damageome proteins when interacting with environmental toxicants. Mechanistic insights into how low-dose arsenic interacts with risk genes are critical knowledge for the prevention, diagnosis, and treatment of arsenic-associated diseases. This project will identify early biomarkers to predict the long-term health impacts of arsenic, and uncover mutational signatures to infer cancer etiology and reveal past arsenic exposure. Lastly, the platform developed in this proposal will be useful for uncovering the effects of environmental toxicants and/or carcinogens with host genes. In addition to its scientific proposal, this application also lays out a comprehensive training plan that will help the candidate achieve his career goal of becoming an independent investigator who will apply his unique background in endogenous DNA damage to better understand genes-exogenous environmental agents (e.g. arsenic) interactions. Further interdisciplinary knowledge in environmental health, formal bioinformatics, and quantitative genomics training, as well as CRISPR and organoid training will put him in a unique position to tackle challenging environmental health research problems. Dr. Chris Amos, Director of the Institute for Clinical and Translational Research at the Baylor College of Medicine will lead a group of co-mentors and advisory committee members to provide advice on research and career development with advancement to a tenure track position.