Core--Protein modulators of toxicity

地核的研究活动强调生物学 在正常细胞中起关键调控分子作用的活性蛋白质 流程。这些研究项目正在为 了解与接触特定化学品有关的风险，并 对某些疾病涉及的分子和细胞过程的知识 疾病。在这个中心主题下包括了几个子主题：受体 蛋白质作为分子传感器，RNA的转录后修饰， 参与谷胱甘肽稳态的蛋白质及其在体内的作用 异种生物的运输和代谢，以及参与细胞周期的蛋白质 将监管作为外源生物的目标。 调查分为七个项目：1)蜂窝和 由AH受体介导的对二恶英的分子反应(T.A.Gasiewicz) 该项目旨在通过以下方式了解分子和细胞基础 其受体介导的毒性与结构相关 卤代烃。次要目标是促进对啊的了解 受体功能，尤其是AhR磷酸化的作用。协作性 项目包括使用AhR反应的报告鼠模型的研究和 AhR的分子作用及其在免疫中的细胞和功能改变 系统。2)TCDD致胸腺萎缩的原因和后果 雌激素(银石)。这项工作的一个主要目标是 含有雌激素受体的细胞类型(S)的鉴定 AHR被TCDD或雌激素激活，导致胸腺萎缩和 免疫抑制。这些研究将检查细胞周期停滞， 参与了细胞凋亡和/或细胞分化的改变 鉴定涉及的基因产物。第二个目标是使用 用小鼠狼疮性肾炎模型鉴定雌激素及TCDD诱导 T细胞发育的改变。3)细胞和分子毒理学研究 血红素降解(M.Maines)。本研究以血红素代谢为研究对象。 途径酶、血红素加氧酶(HO)和胆绿素还原酶(BVR) 阐明血红素降解产物的生理功能。这些 研究人员正在研究HO在大脑和大脑中的生物学功能 心血管系统。正在测试的一个假设是HO的调制 外源性和内源性感受器的活动可能参与类固醇的介导 大脑中涉及记忆和记忆的区域的神经元退化 学习。其他研究表明，通过HO产生的CO可能是 肾毒性所致心血管系统损害防御的研究进展 探员们。BVR在大脑中作为对抗氧化剂的防御机制的作用。 4)酒精对RNA加工的改变及其在动脉粥样硬化中的作用 疾病(H·史密斯)。本研究涉及纯化和分子生物学研究。 参与RNA编辑的辅助蛋白基因的克隆。其他内容 研究正在验证酒精刺激载脂蛋白B mRNA的假设 编辑结果来自于参与mRNA编辑的酶/因子的变化， 5)谷胱甘肽依赖的代谢和质膜运输 外源生物(N.Ballatori)。本研究的重点是身份识别。 以及介导谷胱甘肽输出的细胞膜蛋白的特性 加合物、相关有机阴离子和谷胱甘肽。这个小组已经证明了Oatp1，a 肝脏正弦有机溶质转运体作为谷胱甘肽/有机转运体的功能 溶质交换器，并阐明了血浆中GSH释放的途径。 其他研究正在确定y-谷氨酰环在硫代尿酸中的作用。 酸的生物合成。N-乙酰半胱氨酸已被确定为一种解毒剂 甲基汞。6)卤代烃的生物活化(M.W.Anders)。 这项研究的一个主要目的是研究谷胱甘肽依赖 卤代烷的生物活化及依赖GSH和b-裂解酶的生物活化 卤代烯烃。半胱氨酸S偶联物诱导细胞毒性及机制的研究 转录因子对细胞氧化还原反应的激活 作为一个可能的步骤，正在考虑中。线粒体作为一种细胞因子的作用 细胞内目标正在评估中。7)辐射敏感性和G2M 肺肿瘤细胞延迟(P.Keng)。需要检验的中心假设是 干扰素-b调节照射后人肺肿瘤细胞的dna修复能力。 DNA链断裂的修复是这些研究的重点和影响 干扰素-b对照射后G2M细胞积聚的影响 调查过了。

The research activities in the Core emphasize biologically active proteins that function as critical regulatory molecules in normal cell processes. These research projects are making contributions toward understanding risk associated with exposures to particular chemicals and to knowledge of the molecular and cellular processes involved in certain diseases. Several sub-themes are included under this central theme: Receptor proteins as molecular sensors, post-transcriptional modification of RNA, proteins involved in Glutathione homeostasis and the role of these in xenobiotic transport and metabolism, and proteins involved in cell cycle regulation as targets for xenobiotics. The investigations are organized into seven projects: 1) Cellular and Molecular Responses to Dioxins Mediated by the Ah Receptor (T. A. Gasiewicz). This project is directed at understanding the molecular and cellular basis by which the Ah receptor mediates the toxicity of structurally-related halogenated hydrocarbons. A secondary objective is to advance knowledge of Ah receptor function especially the role of AhR phosphorylation. Collaborative projects include studies using an AhR-responsive reporter mouse model and molecular actions of AhR and cellular and functional alterations in the immune system. 2) Causes and Consequences of Thymic Atrophy Induced by TCDD and Estrogens (A. E. Silverstone). A major objective of this work is the identification of the cell type(s) that contain the estrogen receptor (ER) and AhR and are activated by TCDD or estrogen to cause thymic atrophy and immunosuppression. These studies will examine either cell cycle arrest, apoptosis, and/or altered cellular differentiation are involved and identification of the gene products involved. A second objective is to use a mouse model of a lupus-like nephritis to identify estrogen and TCDD-induced alterations in T-cell development. 3) Cellular and Molecular Toxicology of Heme Degradation (M. Maines). This research focuses on the heme metabolic pathway enzymes, heme oxygenase (HO) and biliverdin reductase (BVR) to elucidate the physiological functions of the heme degradation products. These studies are examining the biological functions of HO in the brain and cardiovascular system. One hypothesis being tested is that modulation of HO activity by exogenous and endogenous sensors may be involved in steroid-mediated degradation of neurons in brain areas involved in memory and learning. Other studies indicate that CO generated via HO may be a component of the cardiovascular system defense against impairment induced by nephrotoxic agents. The role of BVR as a defense mechanism against oxidants in the brain. 4) Alteration in RNA processing by Alcohol and its Role in Atherogenic Diseases (H. Smith). This research involves the purification and molecular cloning of auxiliary protein genes involved in RNA editing. Additional studies are testing the hypothesis that ethanol stimulation of apoB mRNA editing results from alteration of enzymes/factors involved in mRNA editing, 5) Glutathione-dependent Metabolism and Plasma Membrane Transport of Xenobiotics (N. Ballatori). The focus of this research is the identification and characterization of cell membrane proteins that mediate the export of GSH adducts, related organic anions and GSH. This group has shown that oatp1, a sinusoidal organic solute transporter in liver functions as a GSH/organic solute exchanger and elucidates a pathway for GSH release in blood plasma. Other studies are defining the role of the y-glutamyl cycle in a mercapturic acid biosynthesis. N-acetylcysteine has been identified as an antidote for methyl mercury. 6) Bioactivation of Halogenated Hydrocarbons (M. W. Anders). A major objective of this research is to investigate the GSH-dependent bioactivation of haloalkanes and the GSH- and b-lyase-dependent bioactivation of haloalkenes. Mechanisms of cysteine S-conjugate induced cytotoxicity and activation of transcription factors in response to changes in cellular redox as a possible step is being considered. The role of mitochondria as an intracellular target is being assessed. 7) Radiation Sensitivity and G2M Delay in Lung Tumor Cells (P. Keng). The central hypothesis to be tested is that IFN-b modulates DNA repair capacity of irradiated human lung tumor cells. The repair of DNA strand breaks is the focus of these studies and the impact of IFN-b on accumulation of cells in G2M following irradiation is being investigated.