Project 2: Epigenomic Actions of Environmental Arsenicals

项目2：环境砷的表观基因组作用

• 批准号: 8253738
• 负责人: Bernard W FUTSCHER
• 金额: $ 16.83万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8253738
• 关键词: Acids; Address; Arsenic; Arsenicals; Arsenites; Biological Assay; Biological Markers; Biological Models; Bladder; Bladder Urothelial Cell; Blinded; Carcinogens; Cardiovascular Diseases; Cell Cycle; Cell Line; Cells; Chronic; Cost Effectiveness Analysis; DNA Methylation; Data; Diabetes Mellitus; Disease; Dose; Environment; Environmental Exposure; Epigenetic Process; Epithelial; Epithelial Cells; Excision; Exposure to; Gene Expression; Gene Expression Profiling; Gene Silencing; Gene Targeting; Generations; Genes; Genome; Genome Scan; Goals; Hazardous Waste; Histone Acetylation; Human; Human Pathology; In Vitro; Incidence; Individual; Investigation; Knowledge; Link; Liver; Lung; MMA(III); Malignant - descriptor; Malignant Conversion; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of urinary bladder; Mediating; Modeling; Non-Malignant; Phenotype; Population; Populations at Risk; Portraits; Prospective Studies; Research; Research Project Grants; Resolution; Risk; Role; Route; Scanning; Seminal; Sensitivity and Specificity; Skin; Specificity; Structure; System; Technology; Testing; Time; Tissues; Toxic effect; Urine; Urothelial Cell; cohort; design; drinking water; epigenomics; genome wide association study; genome-wide; in vitro Model; insight; pollutant; remediation; research study; stressor

Exposure to environmental arsenicals has been linked to a number of human pathologies, include bladder and lung cancer. We hypothesize that arsenical-mediated perturbation of the epigenetic landscape is an important factor that drives malignant progression. Three integrated specific aims are described in this proposal will address this hypothesis from a gene to genome wide analysis, and from in vitro to "real world" settings. Aim 1 is designed to develop epigenetic targets as biomarkers of arsenical exposure. Preliminary epigenome-wide scanning studies of urine sediments from individuals with known exposure levels in their drinking water have identified candidate epigenetic biomarkers are correlated with arsenical exposure level. The utility of these candidate biomarkers will be evaluated using high sensitivity, high resolution technologies in a new cohort population. Aim 2 will determine if arsenicals produce common perturbations to the epigenomic landscape in their distinct epithelial targets. Experimental strategies of arsenical exposure that caused malignant transformation of urothelial cells will be expanded to lung epithelial model systems. Results from these experiments will help determine if there are seminal epigenetic changes that are common to epithelial malignant transformation in general, as well as the epigenetic changes that display tissue-origin specificity. Aim 3 will provide a detailed investigation of the phenotypic consequences of epigenetic gene inactivation of an arsenical target gene, G0S2, which is closely linked to the malignant transformation of urothelial cells. If our hypothesis is correct, then results from these studies will provide new insights into the mechanisms of their chronic arsenical exposure, as well as serve as a platform for inquiries into other, non-cancer, arsenic-induced human pathologies, such as diabetes and cardiovascular disease.

接触环境砷与许多人类疾病有关，包括膀胱癌和肺癌。我们假设砷介导的表观遗传景观扰动是驱动恶性进展的重要因素。该提案描述了三个综合的具体目标，将解决从基因到全基因组分析、从体外到“现实世界”设置的这一假设。目标 1 旨在开发表观遗传目标作为砷暴露的生物标志物。对已知暴露水平的个体的尿液沉积物进行初步全表观基因组扫描研究 饮用水已确定候选表观遗传生物标志物与砷暴露水平相关。这些候选生物标志物的效用将在新的队列人群中使用高灵敏度、高分辨率技术进行评估。目标 2 将确定砷是否对其不同上皮靶点的表观基因组景观产生常见的扰动。砷暴露导致尿路上皮细胞恶性转化的实验策略将扩展到肺上皮模型系统。这些实验的结果将有助于确定是否存在上皮恶性转化所常见的精液表观遗传变化，以及显示组织起源特异性的表观遗传变化。目标 3 将详细研究砷靶基因 G0S2 的表观遗传基因失活的表型后果，该基因与尿路上皮细胞的恶性转化密切相关。如果我们的假设是正确的，那么这些研究的结果将为了解慢性砷暴露的机制提供新的见解，并作为调查其他非癌症、砷诱发的人类病理的平台，例如糖尿病和心血管疾病。