Role of Enzyme Induction in Cancer Chemoprevention

酶诱导在癌症化学预防中的作用

• 批准号: 6999702
• 负责人: THOMAS W KENSLER
• 金额: $ 39.91万
• 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/6999702
• 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：（申请人提供）拟议研究的总体目标 是为了评估第二阶段酶的功能意义， 化学保护各种各样的化学制剂保护动物 对抗许多不同类型的致癌物的肿瘤效应。许多 这些化学保护剂通过选择性地 诱导（通过增强转录）2期和抗氧化基因， 去毒DNA损伤形式的亲电子终极致癌物， 自由基这些保护性基因中的大多数似乎是通过 抗氧化反应元件（Antioxidant Response Element，ARE）转录因子 其依次与ARE结合，并包括Nrf 2和几种 小Maf蛋白在这个项目中，我们试图使用分子遗传学方法， 为了验证这一假设，即诱导基因的重要性 临床相关的2期酶诱导剂的化学保护功效 （异硫氰酸酯和二硫代硫酮）至少部分通过以下途径介导： 激活NRF 2。目的1是为了研究Nrf 2的作用 伴侣，Keapi，作为第2阶段酶诱导的传感器，并建立 该靶标在信号传导2期基因表达中的作用。AIM 2旨在使用 微阵列技术，以确定哪些基因是通过Nrf 2诱导的 通过比较野生型和nrJ 2突变小鼠中的表达模式来研究nrJ 2通路。 目的3将评估第2阶段和抗氧化酶诱导的重要性 化学保护使用基因破坏的小鼠，nrJ 2，keapi和 MAF无效基因型对我们的铅保护剂体内酶诱导的影响（例如， 萝卜硫素和奥替普拉）及其作为抗肿瘤药物的化学保护功效 将评价实验致癌作用。总体而言， 涵盖从分子/遗传系统到各种实验系统 基因敲除小鼠的致癌易感性。这些研究将 牢固确立诱导2相和抗氧化的作用 化学保护中的酶/蛋白质。了解各种机制， 化学保护剂与传感蛋白相互作用，与ARE通讯， 信号酶诱导将有助于识别和设计更多的 有效和特异性的酶诱导剂，并增强其在人体中的有效使用。