ABERRATIONS IN GENE EXPRESSION IN ARSENIC-TREATED HUMAN EPIDERMAL CELLS

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 砷是一种公认的环境毒物，主要针对人体皮肤，长期接触砷主要通过饮用水与皮肤癌风险增加相关。在这项初步研究中，我们建议研究慢性三氧化二砷暴露浓度对角质形成细胞系全基因组表达谱的时程变化。我们假设，在长期暴露于三氧化二砷处理的细胞中，模拟角质形成细胞的分化，三氧化二砷的毒性损伤将导致基因表达的变化，从而导致癌症的发生。在第一年，我们专注于识别和优先选择已知与砷相互作用的基因，这些基因可能会影响个体对砷引起的皮肤损伤的易感性。因此，下面的目标是确定单核苷酸多态(SNPs)对已知与砷相互作用的基因的功能影响。我们整合了比较毒理基因组学数据库中1,400多个已知与砷相互作用的基因的数据，这些基因与环境基因组计划和Entrez数据库SNP以基因为中心的数据相结合。我们的数据集成方法根据相关的功能影响对13,400多个SNP进行了分类：帧偏移、错义、无稽之谈和同义词。此外，我们还确定了碱基切除DNA修复途径中的SNPs亚群，如XRCC1、hOGG1和APEX1，它们可能影响个体对砷引起的皮肤损伤的易感性。在第二年，将确定对慢性砷暴露做出反应的功能定义的砷相互作用基因表达的异常。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Arsenic, a recognized environmental toxicant targets the human skin and long-term exposure to arsenic principally through drinking water has been correlated with increased risk to skin cancer. In this pilot study, we propose to investigate the time course alteration in genome-wide expression profiles of keratinocyte cell line to chronic exposure concentrations of arsenic trioxide. We hypothesize that in chronically exposed arsenic trioxide treated cells over a time course of two weeks, mimicking keratinocyte differentiation, toxic insult by arsenic trioxide will cause alterations in gene expression leading to carcinogenesis. In the first year, we have focused on identifying and prioritizing genes known to interact with arsenic that may influence an individual's susceptibility to arsenic-induced skin lesions. Thus the following objective was to determine the functional impact of the location of single nucleotide polymorphisms (SNPs) on genes known to interact with arsenic. We have integrated data on over 1,400 genes curated in the Comparative Toxicogenomics Database and known to interact with arsenic with gene-centric data from the Environmental Genome Project and the Entrez dbSNP. Our data integration approach classed over 13,400 SNPs by associated functional impacts: frame shift, missense, nonsense and synonymous. Furthermore, we identified subsets of SNPs in the base excision DNA repair pathway such as XRCC1, hOGG1 and APEX1, that may influence individual susceptibility to arsenic-induced skin lesions. In the second year, the aberrations in the expression of functionally-defined arsenic-interacting genes in response to chronic exposures to arsenic will be determined.