Environmental pollutants & oxidative stress

环境污染物

• 批准号: 6667483
• 负责人: Michael Karin
• 金额: $ 17.5万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6667483
• 关键词: arsenic; biological models; carbon tetrachloride; cell line; chemical kinetics; environmental toxicology; enzyme activity; gene environment interaction; gene expression; gene induction /repression; gene targeting; genetic strain; genetically modified animals; hazardous substances; laboratory mouse; model design /development; oxidative stress; protein kinase; tissue /cell culture; transcription factor

Many Superfund site toxicants exert their chronic toxicity by causing damage to cellular macromolecules via oxidative stress. Exposure to such pro-oxidants also results in induction of a gene expression program whose primary function is to protect cells from oxidative stress. Little is known about the components of the mammalian oxidative stress response and its regulatory logic. To rectify these deficiencies, Project 1 will use a variety of genetic, cell biological and biochemical approaches to investigate the role of already identified stress activated protein kinases in the mammalian response to oxidative stress, identify new components of this induction responses and determine the mechanism of gene induction by a few model toxicants found at Superfund sites, such as arsenite and carbon tetrachloride. We will also search for new regulatory molecules, including protein kinases and transcription factors, involved in the oxidative stress response. Once identified, the pathophysiological function of these molecules will be analyzed through generation of constitutive and conditional knockout mouse mutants. We will investigate how such genetic alterations affect the ability of these animals or cells derived from them to withstand exposure to Superfund site toxicants that are believed to act via induction of oxidative stress. In addition to elucidating the basic regulatory logic underlying the mammalian response to oxidative stress, this project will have two practical outcomes relevant to the mission of the Superfund Research Program; it will create: 1) gene arrays, cell lines and transgenic mice that can be used as biosensors for monitoring exposure to toxicants that cause oxidative stress; 2) strains of mice that are deficient in activation of the protective response to oxidative stress. Such mice should be supersensitive to pro-oxidants and thus will facilitate the detection and evaluation of new suspected toxicants and mixtures of chemicals from Superfund Sites for their ability to cause oxidative stress mediated toxicity. To accomplish these goals this project will collaborate and interact with Projects 2, 3, 4 and 5 and will rely on all research support cores.

许多超级基金部位的毒性通过氧化应激损害了细胞大分子，从而施加了慢性毒性。暴露于这种促氧化剂还会导致诱导基因表达程序，其主要功能是保护细胞免受氧化应激。关于哺乳动物氧化应激反应及其调节逻辑的成分知之甚少。为了纠正这些缺陷，项目1将使用多种遗传，细胞生物学和生化方法来研究已经鉴定的应激激活蛋白激酶在哺乳动物对氧化应激的反应中的作用，并确定这种归纳诱导反应的新成分，并通过少数模型的毒性在超级领域（例如，诸如超级养育者）（例如carsenite and carsenite）确定基因诱导的机制。我们还将搜索与氧化应激反应有关的新调节分子，包括蛋白激酶和转录因子。一旦确定，这些分子的病理生理功能将通过产生组成型和条件基因敲除小鼠突变体进行分析。我们将研究这种遗传变化如何影响这些动物或细胞从它们衍生出的超级基金部位毒物的能力，这些毒物被认为是通过诱导氧化应激而起作用的。 除了阐明哺乳动物对氧化应激反应的基本法规逻辑外，该项目还将具有与超级基金研究计划的任务有关的两个实际结果。它将创建：1）基因阵列，细胞系和转基因小鼠，可以用作监测导致氧化应激的毒物的生物传感器； 2）缺乏对氧化应激的保护性反应的小鼠菌株。这样的小鼠应对促氧化剂具有超敏感性，因此将促进和评估超级基金部位的新的可疑毒物和化学物质混合物，以引起氧化应激介导的毒性。为了实现这些目标，该项目将协作并与项目2、3、4和5互动，并将依靠所有研究支持核心。