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.

项目总结