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

水通道蛋白 3 在砷诱导的 DNA 损伤和突变中的作用

• 批准号: 10634794
• 负责人: Jun Xia
• 金额: $ 24.9万
• 依托单位: CREIGHTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10634794
• 关键词: Acute; Advisory Committees; Affect; Arsenic; Bioinformatics; Biological; Biological Assay; Cancer Etiology; Carcinogens; Cardiovascular Diseases; Cell Line; Cells; Chronic; Clinical Research; Clustered Regularly Interspaced Short Palindromic Repeats; Colon; Committee Members; DNA; DNA Damage; DNA Repair; DNA Repair Disorder; DNA Sequence Alteration; Data; Diagnosis; Disease; Dose; Dyes; Environmental Health; Etiology; Foundations; Frequencies; Genes; Genetic; Genetic study; Genome engineering; Genomic Instability; Genomics; Geography; Goals; Health; Human; Human Cell Line; Individual; Institutes; Knowledge; Lead; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Maps; Measures; Medicine; Mentors; Methods; Modeling; Molecular; Mus; Mutagenesis; Mutation; Neurodegenerative Disorders; Noise; Organoids; Persons; Population; Positioning Attribute; Predisposition; Prevention; Protein Family; Proteins; Reactive Oxygen Species; Recurrence; Research; Research Personnel; Resolution; Risk; Role; Signal Transduction; Technology; Testing; Tissues; Toxic Environmental Substances; Toxicology; Toxin; Training; Translational Research; aquaporin 3; carcinogenesis; career; career development; chromatin immunoprecipitation; cohort; college; drinking water; early detection biomarkers; environmental agent; exome sequencing; genome sequencing; genomic biomarker; insight; live cell imaging; mutant; oxidative DNA damage; research and development; risk variant; tenure track; water channel; whole genome

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.

项目摘要 砷在饮用水中是一种广泛的毒素，影响数百万人，增加了 神经退行性和心血管疾病和癌症。高剂量的砷会导致DNA损伤和 基因组不稳定性。但是，与低剂量砷有关的健康影响是有争议的。最近， 我们发现大型DNA损害蛋白（DDP）的大型网络促进了DNA损伤和基因组 不稳定性（Xia等，Cell，2019）。我们还发现Aquaporin 3（AQP3）是一种新的与肺癌相关的DDP。 该应用描述了AQP3与低剂量砷相互作用以促进DNA的机制 损坏，一种MAP AQP3的方法，砷引起的双链断裂（DSB）热点以及相关的方法 人类细胞和人群中的突变特征。具体而言，它将（1）提供机械见解 AQP3如何增强砷诱导的DNA损伤，（2）由AQP3和低剂量砷引起的MAP DSB 相互作用，（3）识别AQP3和砷诱导的基因组不稳定性和突变特征。这 提出的研究将在内源性DNA损伤和DNA损害蛋白中带来功能 与环境有毒物质相互作用。低剂量砷与风险相互作用的机械洞察力 基因是预防，诊断和治疗砷相关疾病的关键知识。这 项目将确定早期的生物标志物，以预测砷的长期健康影响，并发现突变 推断癌症病因并揭示过去的砷暴露的签名。最后，平台在此开发 提案将有助于发现与宿主的环境有毒物质和/或致癌物的影响 基因。除了其科学建议外，该应用程序还制定了一项全面的培训计划 帮助候选人实现自己的职业目标，成为一名独立调查员，他将运用他的独特 内源性DNA损伤的背景，以更好地了解基因过源环境药物（例如 砷的相互作用。在环境健康，正式生物信息学和 定量基因组学培训以及CRISPR和类器官培训将使他处于独特的位置 解决具有挑战性的环境健康研究问题。临床研究所主任克里斯·阿莫斯（Chris Amos）博士 贝勒医学院的翻译研究将领导一群联合会和咨询 委员会成员提供有关研究和职业发展的建议 轨道位置。