Cellular Responses to Oxidative Stress in Models of Colon Cancer Development

这一跨学科翻译研究计划的中心主题是肾毒性人类致癌物马兜铃酸(AA)的分子毒理学。我们将采用跨学科的方法(化学、细胞生理学和遗传学)来研究马兜铃酸肾病的发病机制，结合分子流行病学和毒素基因组学来深入了解导致这种广泛疾病的易感性或耐药性的遗传因素。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，这项研究 在总体上为环境疾病提供了一种机械化的战略方法。 我们的长期目标是：(A)建立马兜铃酸对人类和动物产生深刻的肾脏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诱变潜力联系起来，并建立通过核苷酸切除修复将其移除的结构-功能关系；(C)利用AAN的小鼠模型来研究AAN的生物转化。 (D)确定AA引起的肾脏近端小管细胞毒性反应的相关基因，区分AA对尿路上皮细胞的遗传毒性效应；(E)剖析AA诱导的肾间质纤维化所涉及的遗传和细胞事件；(F)利用分子流行病学和毒性基因组学方法，探讨类似疾病地方性肾病及其相关的发病机制。 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对公众健康产生直接影响。最明显的是，建立饮食摄入马兜铃酸与肾病和尿路上皮癌风险增加之间的关系建议了预防策略，这些策略将减轻并有可能从流行区域消除这种肾病。此外，由于纤维化是一个与终末期肾病、间质性肺疾病、肝硬变和心脏病相关的不可逆转的过程，我们的研究 可能对导致美国和世界各地发病率和死亡率的疾病造成影响。

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.