权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Epigenetic Remodeling by Environmental Arsenicals

环境砷的表观遗传重塑

基本信息

批准号：
7659420
负责人：
Bernard W FUTSCHER
金额：
$ 22.51万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-09-27 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7659420
关键词：
Acids Arsenic Arsenicals Arsenites Back Biological Markers Bladder Carcinogens Cardiovascular Diseases Cell Line Cells DNA Methylation Data Diabetes Mellitus Disease Dose Environmental Exposure Epigenetic Process Etiology Excision Exposure to Gene Expression Gene Expression Profiling Generations Genes Genome Genome Scan Goals Health Human Human Pathology Incidence Individual Knowledge Link Literature Liver Lung MMA(III)Malignant - descriptor Malignant Conversion Malignant Neoplasms Malignant neoplasm of urinary bladder Mediating Metals Modeling Phenotype Play Population Populations at Risk Portraits Proto-Oncogenes Regulation Reporting Research Research Personnel Research Project Grants Resolution Role Route Scanning Seminal Skin Structure Technology Testing Time Toxic effect Urothelial Cell Variant base cellular targeting cohort design drinking water epigenomics exposed human population genome-wide in vitro Model insight malignant phenotype programs research study response stressor tumorigenic

项目摘要

DESCRIPTION (provided by applicant): Environmental exposure to arsenic and its metabolites is a significant health concern to US and world populations, playing a causative role in the etiology of human pathologies, including cancer. The long-term goal of the proposed study is designed to identify mechanisms of toxicity that are a result of environmental exposures to arsenicals. It is hypothesized that arsenical toxicity, in part, is mediated through its disruption of the normal epigenetic state of cells, and this hypothesis is based on reports in the extant literature as well as these preliminary studies. This premise will be tested using advanced epigenetic technologies to analyze models of arsenical exposure. These models range from in vitro models of arsenical-mediated malignant transformation of human uroepithelial cells to well-characterized, ethnically important human populations exposed to known levels of environmental arsenicals through drinking water. Through three specific aims the effects of arsenicals on epigenetic regulation from the level of the individual gene to the level of the entire genome will be tested. The aims are to: 1) Investigate the mechanisms and phenotypic consequences of epigenetic activation of Wnt5a gene that has been observed in an in vitro model of arsenical-induced malignant transformation. 2) Identify the decisive changes in the epigenomic landscape over the time course of arsenical induced malignant conversion of the immortalized human bladder cell UROtsa, and determine the stability of these changes after removal of this stressor. 3) Identify epigenetic targets of arsenic in human populations exposed to known levels of arsenic in their drinking water. While this research application focuses on the epigenetic perturbations induced by arsenicals with respect to human cancer, it is likely that if the hypothesis is backed by the studies, that of arsenical induced epigenetic changes as a mechanism of long-term toxicity, then the knowledge generated will likely extend to other metal-induced human pathologies, such as diabetes and cardiovascular disease.

描述（由申请人提供）：砷及其代谢物的环境暴露是美国和世界人口的一个重大健康问题，在人类病理学（包括癌症）的病因学中起着致病作用。拟议研究的长期目标是确定环境暴露于砷的毒性机制。据推测，砷的毒性，在某种程度上，是通过其破坏细胞的正常表观遗传状态介导的，这一假设是基于现有文献中的报告，以及这些初步研究。这一前提将使用先进的表观遗传学技术进行测试，以分析砷暴露模型。这些模型的范围从砷介导的人类泌尿上皮细胞恶性转化的体外模型，到通过饮用水暴露于已知水平的环境砷的具有良好特征的、在种族上重要的人群。通过三个具体目标，砷对表观遗传调控的影响，从单个基因的水平，整个基因组的水平将被测试。其目的是：1）研究在砷诱导的恶性转化的体外模型中观察到的Wnt5a基因的表观遗传激活的机制和表型后果。2)确定砷诱导的永生化人膀胱细胞UROtsa恶性转化的时间过程中表观基因组景观的决定性变化，并确定去除这种应激源后这些变化的稳定性。3)确定暴露于已知饮用水中砷水平的人群中砷的表观遗传靶点。虽然这项研究应用的重点是砷剂引起的人类癌症的表观遗传扰动，但如果这一假设得到研究的支持，即砷剂引起的表观遗传变化是一种长期毒性机制，那么所产生的知识可能会扩展到其他金属引起的人类病理学，如糖尿病和心血管疾病。