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：(申请人提供)拟议研究的总体目标 是为了评估第二阶段酶在人体内的功能意义 化学保护。保护动物的化学药剂种类繁多 对抗多种不同类型致癌物的致癌作用。许多. 这些化学保护剂通过选择性地发挥其抗癌作用。 诱导(通过增强转录)阶段2和抗氧化基因 为亲电终极致癌物的DNA损伤形式解毒，并 自由基。这些保护性基因中的大多数似乎是通过一种 常见的增强剂，抗氧化剂反应元件(ARE)。转录因子 它们依次与ARE结合，并包括NRF2和几个 小的Maf蛋白。在这个项目中，我们试图使用分子遗传学方法 为了检验这样一种假设，即基因的诱导对 临床相关2相酶诱导剂的化学保护作用 (异硫氰酸酯和二硫代硫酮)至少部分地通过 Nrf2的激活。AIM 1旨在研究NRF2的作用 分子伴侣Keapi作为2相酶诱导的感受器，建立了 该靶点在信号转导阶段2基因表达中的作用。AIM2寻求使用 微阵列技术识别哪些基因是通过Nrf2诱导的 通过比较野生型和nrJ2突变小鼠的表达模式。 目标3将评估第二阶段和抗氧化酶诱导的重要性。 在化学保护中。在基因干扰小鼠中，nrJ2、keapi和 我们的铅保护剂在体内诱导酶的MAF零基因(例如， 萝卜硫素和奥替拉兹)及其作为抑制剂的化学保护作用 将对实验性的致癌作用进行评估。总的来说，这些方法 涵盖了从分子/遗传系统到各种实验系统 对基因敲除小鼠致癌的易感性。这些研究将 牢固确立诱导2期和抗氧化的作用 化学保护中的酶/蛋白质。关于机制的知识 化学保护剂与感受器蛋白(S)相互作用，与ARE进行通信 信号酶诱导将有助于鉴定和设计更多 有效和特定的酶诱导剂，并提高其在人类中的有效利用。