Role of Nrf2 Cross-Talk in Cancer Chemoprevention

Nrf2 串扰在癌症化学预防中的作用

基本信息

批准号：
8451295
负责人：
THOMAS W KENSLER
金额：
$ 35.1万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-12-21 至 2017-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8451295
关键词：
Acetaminophen Affect Albumins Animals Anti-Inflammatory Agents Anti-inflammatory Antioxidants Autophagocytosis Benefits and Risks Binding Carcinogens Cell Survival Cells Chemicals Chemoprevention Chemopreventive Agent Chemoprotection Chemoprotective Agent Chronic DNA Repair Excision Food Gene Targeting Genes Genetic Goals Heat shock proteins Hepatocarcinogenesis Hepatocyte Human Kinetics Liver Liver Regeneration Liver diseases Luciferases Mediating Molecular Molecular Genetics Mus Natural regeneration Nucleotides Oncogenes Outcome Partial Hepatectomy Pathway interactions Pharmacodynamics Prevention Promoter Regions Recovery Reporter Research Resistance Response Elements Role Rosa Signal Pathway Signal Transduction Stress Sulforaphane System Testing Toxic effect Transgenic Mice Transgenic Model Transplantation Urokinase Wild Type Mouse Work base cancer chemoprevention carcinogenesis chemical carcinogenesis chemical genetics detoxication in vivo liver injury major urinary proteins multicatalytic endopeptidase complex neoplastic cell promoter protective effect protein misfolding repaired research study response small molecule stress protein tissue repair transcription factor tumor growth

项目摘要

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.

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，有助于使动物抵抗化学致癌和其他形式的毒性，而该通路的破坏会加剧这些结果。该途径可以被用于化学预防的巯基反应性小分子药理学和食品制剂激活，通常通过转录因子 Nrf2 与抗氧化反应元件的直接结合来调节一系列细胞保护基因的诱导表达。目标基因的启动子区域。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方式对化学应激提供多层次的综合反应：（i）通过诱导抗氧化、抗炎和致癌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、遗传和化学方法来检验这样的假设：Nrf2 介导的化学保护不仅反映了其直接靶基因的激活，而且重要的是与影响细胞命运的其他适应性反应信号网络（例如 Notch1）进行了串扰。拟议研究的总体目标有两个：评估通路串扰的潜在机制和后果，并评估慢性诱导 Nrf2 反应的功能意义和可能的不良影响，以促进识别和利用安全、有效的化学预防剂。