Role of Enzyme Induction in Cancer Chemoprevention

酶诱导在癌症化学预防中的作用

• 批准号: 6831207
• 负责人: THOMAS W KENSLER
• 金额: $ 40.88万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-12-21 至 2006-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831207
• 关键词: cancer prevention; chemoprevention; drug metabolism; enzyme activity; enzyme induction /repression; gene targeting; genetically modified animals; isothiocyanates; laboratory mouse; liver metabolism; microarray technology; molecular chaperones; synthetic enzyme; transcription factor

DESCRIPTION: (PROVIDED BY APPLICANT) The overall goals of the proposed studies are to assess the functional significance of phase 2 enzymes in chemoprotection. An extraordinary variety of chemical agents protect animals against the neoplastic effects of many different types of carcinogens. Many of these chemoprotectors exert their anticarcinogenic effects by selectively inducing (by enhanced transcription) phase 2 and antioxidative genes that serve to detoxify the DNA-damaging forms of electrophilic ultimate carcinogens and free radicals. Most of these protective genes appear to be induced through a common enhancer, the Antioxidant Response Element (ARE). Transcription factors which in turn bind to the ARE are being identified and include Nrf2 and several small Maf proteins. In this project we seek to use molecular genetic approaches to test the hypothesis that the induction of genes important for the chemoprotective efficacy of clinically relevant phase 2 enzyme inducers (isothiocyanates and dithiolethiones) is mediated, at least in part, through activation of Nrf2. Aim 1 is designed to investigate the role of the Nrf2 chaperone, Keapi, as the sensor for phase 2 enzyme induction, and establish the role of this target in signaling phase 2 gene expression. Aim2 seeks to use microarray technology to identify which genes are induced through the Nrf2 pathway by comparing patterns of expression in wild-type and nrJ2-mutant mice. Aim 3 will assess the importance of phase 2 and antioxidative enzyme induction in chemoprotection. Using gene-disrupted mice, the influence of nrJ2, keapi and maf null genotypes on enzyme induction in vivo by our lead protectors (e.g., sulforaphane and oltipraz) and their chemoprotective efficacy as inhibitors of experimental carcinogenesis will be evaluated. Collectively, the approaches encompass a broad range of experimental systems from molecular/genetic systems to susceptibility to carcinogenesis in gene knockout mice. These studies will firmly establish the role of induction of phase 2 and antioxidative enzymes/proteins in chemoprotection. Knowledge of the mechanisms by which chemoprotectors interact with sensor protein(s) to communicate to the ARE to signal enzyme induction will facilitate the identification and design of more potent and specific enzyme inducers and enhance their effective use in humans.

描述：（由申请人提供）拟议研究的总体目标 评估2阶段酶在中的功能意义 化学保护。各种各样的化学剂保护动物 反对许多不同类型的致癌物的肿瘤作用。许多 这些化学保护器通过有选择性地发挥其抗癌作用 诱导（通过增强的转录）阶段2和使用的抗氧化基因 排毒电力最终致癌物的DNA破坏形式和 自由基。这些保护基因中的大多数似乎是通过a诱导的 共同增强子，抗氧化剂反应元件（AS）。转录因子 这又被确定为绑定并包括NRF2和几个 小型MAF蛋白。在这个项目中，我们试图使用分子遗传方法 测试基因诱导对 临床相关期2酶诱导剂的化学保护功效 （异硫氰酸盐和二硫代）至少在某种程度上通过 NRF2的激活。 AIM 1旨在研究NRF2的作用 伴侣，Keapi，作为第2阶段酶诱导的传感器，并建立 该目标在信号传导阶段2基因表达中的作用。 AIM2试图使用 微阵列技术以识别通过NRF2诱导哪些基因 通过比较野生型和NRJ2突变小鼠中表达模式的途径。 AIM 3将评估第2阶段和抗氧化酶诱导的重要性 在化学保护中。使用基因脱离的小鼠，NRJ2，KEAPI和 我们的铅保护因子（例如， Sulforaphane和Oltipraz）及其化学保护功效作为抑制剂 将评估实验性致癌作用。总体而言，这些方法 包括分子/遗传系统的广泛实验系统 在基因基因敲除小鼠中对癌变的敏感性。这些研究会 牢固确立诱导2阶段和抗氧化的作用 化学保护中的酶/蛋白质。了解其机制 Chemoprotector与传感器蛋白相互作用以与蛋白进行通信 信号酶诱导将有助于识别和设计更多 有效的特定酶诱导剂，并增强其在人类中的有效使用。