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: 10283270
• 负责人: Jun Xia
• 金额: $ 10.34万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10283270
• 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; 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.

项目概要 砷是饮用水中一种广泛存在的毒素，影响数百万人，增加了患病风险 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 基因组不稳定。然而，低剂量砷对健康的影响存在争议。最近， 我们发现 DNA 损伤蛋白 (DDP) 的大型网络会促进 DNA 损伤和基因组损伤 不稳定性（Xia 等人，Cell 2019）。我们还发现水通道蛋白 3 (AQP3) 是一种新的肺癌相关 DDP。 该应用描述了 AQP3 与低剂量砷相互作用促进 DNA 的机制 损伤、绘制 AQP3、砷诱导的双链断裂 (DSB) 热点以及相关的方法 人类细胞和群体中的突变特征。具体来说，它将 (1) 提供以下方面的机制见解： AQP3 如何增强砷诱导的 DNA 损伤，(2) 绘制 AQP3 和低剂量砷引起的 DSB 图谱 (3) 识别 AQP3 和砷诱导的基因组不稳定性和突变特征。这 拟议的研究将为内源性 DNA 损伤和 DNA 损伤组蛋白带来功能 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来预测砷对健康的长期影响，并揭示突变 推断癌症病因并揭示过去砷暴露的特征。最后，本次开发的平台 该提案将有助于揭示环境毒物和/或致癌物对宿主的影响 基因。除了科学建议外，该应用程序还制定了全面的培训计划，将 帮助候选人实现成为一名独立调查员的职业目标，并运用其独特的能力 内源性 DNA 损伤的背景，以更好地了解基因-外源环境因素（例如 砷）相互作用。进一步了解环境健康、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地位 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组共同导师和顾问 委员会成员就研究和职业发展以及晋升终身职位提供建议 轨道位置。