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

项目总结 砷是饮用水中一种广泛存在的毒素，影响着数百万人，增加了患上 神经退行性疾病、心血管疾病和癌症。高剂量的砷会导致DNA损伤和 基因组不稳定。然而，低剂量砷对健康的影响是有争议的。最近， 我们发现，DNA损伤组蛋白(DDP)的大网络促进了DNA损伤和基因组 不稳定(Xia et al.单元格2019)。我们还发现水通道蛋白3(AQP3)是一种新的肺癌相关顺铂。 这项应用描述了AQP3与低剂量砷相互作用促进DNA的机制 损伤，一种定位AQP3，砷诱导的双链断裂(DSB)热点的方法，以及相关 人类细胞和种群中的突变特征。具体地说，它将(1)提供对 AQP3如何增强砷诱导的DNA损伤，(2)AQP3和低剂量砷引起的MAP双链断裂 相互作用，以及(3)确定AQP3和砷诱导的基因组不稳定和突变特征。这个 拟议的研究将在以下情况下对内源性DNA损伤和DNA损伤蛋白质产生作用 与环境毒物相互作用。关于低剂量砷如何与风险相互作用的机械论见解 基因是预防、诊断和治疗砷相关疾病的关键知识。这 该项目将识别早期生物标记物，以预测砷对健康的长期影响，并发现突变 推断癌症病因和揭示既往接触砷的信号。最后，本文所开发的平台 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。除了它的科学建议，这项申请还列出了一个全面的培训计划，将 帮助应聘者实现他的职业目标，成为一名独立调查员，他将运用自己独特的 内源性DNA损伤背景以更好地了解基因--外源性环境因子(例如 砷)相互作用。进一步了解环境健康、正规生物信息学和 定量基因组学培训，以及CRISPR和有机体培训将使他处于独特的地位 解决具有挑战性的环境健康研究问题。克里斯·阿莫斯博士，临床研究所所长 贝勒医学院的翻译研究将领导一组共同导师和顾问 委员会成员须就研究和职业发展提供意见，并提拔至终身教职 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.