Role of Nrf2 Cross-Talk in Cancer Chemoprevention

描述（由申请人提供）：Keap1-Nrf2信号通路的激活是对环境和内源性应激的适应性反应，有助于使动物对化学致癌和其他形式的毒性产生抗性，而该通路的破坏会加剧这些结果。这一途径可被用于化学预防的巯基反应性、小分子药理学和基于食物的药物激活，通常通过转录因子Nrf2直接结合靶基因启动子区域的抗氧化反应元件来调节一系列细胞保护基因的诱导表达。然而，我们最近的工作表明，一些保护作用可能是通过与影响细胞存活和细胞命运其他方面的其他途径的串扰间接介导的。这些相互作用通过以下途径提供了对化学胁迫的多层综合反应：(i)通过诱导抗氧化、抗炎和致癌物质解毒基因来预防大分子损伤；（ii）诱导大分子损伤识别、修复/去除系统；（iii）组织修复/再生途径的激活。在这个项目中，我们试图使用分子、遗传和化学方法来验证Nrf2介导的化学保护既反映了其直接靶基因的激活，也重要地与其他影响细胞命运的适应性反应信号网络（如Notch1）相互作用的假设。拟议研究的总体目标有两个方面：评估通路串扰的潜在机制和后果，评估慢性诱导Nrf2反应的功能意义和可能的不良影响，以促进安全有效的化学预防药物的识别和利用。

DESCRIPTION (provided by applicant): Activation of the Keap1-Nrf2 signaling pathway is an adaptive response to environmental and endogenous stresses and serves to render animals resistant to chemical carcinogenesis and other forms of toxicity, whereas disruption of the pathway exacerbates these outcomes. This pathway, which can be activated by sulfhydryl reactive, small-molecule pharmacologic and food-based agents used in chemoprevention, regulates the inducible expression of an extended battery of cytoprotective genes, often by direct binding of the transcription factor Nrf2 to antioxidant response elements in the promoter regions of target genes. However, our recent work indicates that some of the protective effects may be mediated indirectly through cross-talk with additional pathways affecting cell survival and other aspects of cell fate. These interactions provide a multi-tiered, integrated response to chemical stresses through: (i) prevention of macromolecular damage through induction of antioxidative, anti-inflammatory and carcinogen detoxication genes; (ii) induction of macromolecular damage recognition, repair/removal systems; and (iii) activation of tissue repair/regeneration pathways. In this project we seek to use molecular, genetic and chemical approaches to test the hypothesis that chemoprotection mediated by Nrf2 reflects both activation of its direct target genes but importantly cross- talk with other adaptive response signaling networks affecting cell fate, such as Notch1. The overall goals of the proposed studies are two-fold: to assess the underlying mechanisms and consequences of pathway cross-talk and to assess the functional significance and possible untoward effects of chronic induction of the Nrf2 response in order to facilitate the identification and utilization of safe, efficacious chemopreventive agents.