Cellular Responses to Oxidative Stress in Models of Colon Cancer Development

这个跨学科的翻译研究计划的中心主题围绕着一个肾毒性的人类致癌物质，马兜铃酸（AA）的分子毒理学。我们将带来一个跨学科的方法（化学，细胞生理学和遗传学）承担马兜铃酸肾病的发病机制，结合分子流行病学和毒理基因组学，以提供深入了解遗传因素，有助于易感性或耐药这种广泛的疾病，。此外，AAN作为目前特发性肾脏疾病和以纤维化为特征的疾病的模型， 提供了一个机械的战略方法，以环境疾病的一般。 我们的长期目标是：（a）建立马兜铃酸在人类和动物中发挥其深刻的肾毒性和遗传毒性作用的分子机制;（B）将AA-DNA加合物的三维结构与这些损伤的致突变潜力联系起来，并建立通过核苷酸切除修复去除这些损伤的结构-功能关系;（c）利用AAN的小鼠模型研究AAN的生物转化。 AA和验证AA-DNA加合物作为暴露和疾病风险的潜在生物标志物;（d）鉴定参与肾近端小管对AA的细胞毒性反应的小鼠和人类基因，将这种单一效应与AA对尿路上皮细胞的遗传毒性效应区分开来;（e）分析AA诱导的肾间质纤维化中涉及的遗传和细胞事件;（f）采用分子流行病学和毒理基因组学方法，探讨一种类似疾病地方性肾病及其相关疾病的发病机制， 尿路上皮癌，并确定控制这种毁灭性疾病发展的基因。 这项研究的结果预计将直接影响公共卫生。最明显的是，建立马兜铃酸饮食暴露与肾病和尿路上皮癌风险增加之间的关系表明，预防策略将减轻并可能消除流行地区的肾病。此外，由于纤维化是与终末期肾病、间质性肺病、肝硬化和心脏病相关的不可逆过程，我们的研究 可能影响美国和世界各地导致发病率和死亡率的疾病。

The central theme of this interdisciplinary translational research program revolves around the molecular toxicology of a nephrotoxic human carcinogen, aristolochic acid (AA). We will bring an interdisciplinary approach (chemistry, cell physiology and genetics) to bear on the pathogenesis of aristolochic acid nephropathy, combining molecular epidemiology and toxicogenomics to provide insights into genetic factors that contribute to susceptibility or resistance to this widespread disease,. Additionally, AAN serves as a model for currently idiopathic kidney diseases and disorders characterized by fibrogenesis, and this research provides a mechanistic strategic approach to environmental diseases in general. Our long-term goals are to: (a) establish the molecular mechanisms by which aristolochic acids exert their profound nephrotoxic and genotoxic effects in humans and animals; (b) relate the 3-D structures of AA-DNA adducts to the mutagenic potential of these lesions and to establish structure-function relationships involved in their removal by nucleotide excision repair; (c) utilize a mouse model of AAN to study biotransformation of AA and to validate AA-DNA adducts as potential biomarkers of exposure and risk of disease; (d) identify mouse and human genes involved in the cytotoxic response of renal proximal tubules to AA, differentiating this singular effect from the genotoxic effects of AA on urothelial cells; (e) dissect the genetic and cellular events involved in AA-induced renal interstitial fibrosis; (f) use molecular epidemiologic and toxicogenomic approaches to explore the pathogenesis of a similar disease, endemic nephropathy, and its associated urothelial cancer, and to identify genes that control development of this devastating disease. Findings emanating from this research are expected to impact directly on public health. Most obviously, establishing the relationship between dietary exposure to aristolochic acid and an increased risk of nephropathy and urothelial cancer suggests preventive strategies that will mitigate and potentially eliminate this nephropathy from the endemic region. In addition, as fibrogenesis is an irreversible process associated with end-stage renal disease, interstitial lung diseases, hepatic cirrhosis and heart disease, our research has the potential to impact disorders responsible for morbidity and mortality in the US and throughout the world.