TOXICOLOGY OF ENVIRONMENTAL CHEMICALS

描述（由申请人提供）： 研究在这个有竞争力的PPG更新，环境化学品的毒性，是重点 关于了解某些环境化学品的毒性机制和 涉及免疫系统、细胞功能、氧化应激的基本生化机制 以及可能因环境化学物质的不利影响而改变的基因表达。 PPG跨学科研究的首要主题是蛋白质-配体，蛋白质-蛋白质 相互作用和细胞信号通路。该PPG将取决于以下组合： 实验策略包括整个动物模型，生物化学和分子生物学 生物学方法;各种生物物理学方法，包括质谱法和动力学 为了解决与免疫系统调节和细胞粘附相关的问题， 细胞外基质;蛋白质的硝化过氧亚硝酸盐;和RA依赖性转录因子的信号通路。这些研究将具体侧重于：（1）确定 TCDD诱导的AhR激活改变了T淋巴细胞中的信号通路， T细胞功能障碍，（2）确定参与细胞调节的机制， 粘附和运动的PDGF，（3）阐明的机制，通过氧化的蛋白质 过氧亚硝基阴离子干扰蛋白质-蛋白质相互作用;（4）探讨GRASP的作用 以及10号染色体上缺失的肿瘤抑制因子、磷酸酶和张力蛋白同源物 （5）阐明RA诱导的PTEN蛋白在信号通路中的作用机制， 动态参与RA受体介导的基因表达诱导的RA，甲氧普烯酸， 和其他激动剂。使用的实验方法包括流式细胞术、UV循环 二向色性、荧光、猝灭和停流动力学，以及开发的新技术 在现有的PPG（ES 00040）下，包括高速细胞分选，差异蛋白水解， 灵敏度分析、H/D交换和奇异值分解用于多状态分析 在平衡状态下展开事件。质谱核心将提供质谱 支持个别项目。5个高度跨学科的项目将回答 关于特定环境化学品对环境的影响的重大未决问题 蛋白质-蛋白质相互作用和重要的细胞信号传导途径。

DESCRIPTION (provided by applicant): Research in this competitive PPG renewal, Toxicity of Environmental Chemicals, is focused on understanding the mechanisms of toxicity of selected environmental chemicals and the basic biochemical mechanisms involving the immune system, cellular function, oxidative stress and gene expression that may be altered through adverse effects of environmental chemicals. The overriding theme of this interdisciplinary research PPG is protein-ligand, protein-protein interactions and cellular signaling pathways. This PPG will depend on a combination of experimental strategies involving whole animal models, and biochemical and molecular biological methods; a variety of biophysical methods including mass spectrometry and kinetics to address questions relating to regulation in the immune system and cell adhesion to the extracellular matrix; nitration of proteins by peroxynitrite; and signaling pathways in RA-dependent transcription factors. These studies will specifically focus on: (1) identifying the signaling pathways in T lymphocytes that are altered by TCDD-induced AhR activation leading to T cell dysfunction, (2) determining the mechanisms involved in the regulation of cell adhesion and motility by PDGF, (3) elucidating the mechanisms by which oxidation of proteins by peroxynitrite interferes with protein-protein interactions, (4) investigating the role of GRASP and the tumor suppressor, phosphatase and tensin homolog deleted on chromosome 10 (PTEN), in signaling pathways induced by RA, and (5) elucidating the mechanisms and dynamics involved in RA receptor-mediated gene expression induced by RA, methoprene acid, and other agonists. Experimental approaches to be used include flow cytometry, UV circular dichroism, fluorescence, quench and stopped-flow kinetics, and new techniques developed under the existing PPG (ES00040), including high speed cell sorting, a differential proteolytic sensitivity assay, H/D exchange, and singular value decomposition for analyzing multistate unfolding events at equilibrium. A Mass Spectrometry Core will provide mass spectrometry support for the individual Projects. The 5 highly interdisciplinary Projects will answer significant unresolved questions concerning the effects of specific environmental chemicals on protein-protein interactions and important cellular signaling pathways.