Dissecting the Signaling Network for Ah Receptor-mediated B-cell Toxicity

对超级基金场所人类接触途径的全面评估表明， 作为Ahr激动剂，对周围居民存在重大风险， 这是研究最少的毒理学终点之一。该项目的主要目标有两个方面：（1） 研究了参与抑制B细胞活化和IgM分泌的基因表达级联反应， 暴露于Ahr激动剂;（2）联合收割机基因表达级联的信息与全面的 对蛋白质相互作用的调查和集中的分子实验，以创建Ahr在B细胞中作用的综合系统水平模型 差分信号网络我们假设B细胞分化网络中的多个节点 都是由AHR监管的通过剖析基因表达级联中的相互关系， 有了一个全面的蛋白质相互作用图谱，我们将能够机械地模拟剂量反应， Ahr B细胞免疫毒性的行为。该假设将使用以下独特组合进行检验： 基因组和计算工具，解剖暴露于Ahr后的转录级联反应， 激动剂并推断细胞信号网络的相应结构以用于计算建模。 该建议的具体目标是：（1）鉴定B细胞基因表达中Ahr依赖性的改变 LPS激活和暴露于原型Ahr激动剂TCDD后的级联反应;（2）表征 Ahr激活对B细胞分化中基因表达的主要变化的直接顺式作用 级联反应;（3）描述初级基因表达事件和次级和 Ahr介导的B细胞分化改变的三级基因表达变化;和（4）联合收割机 关于Ahr调节的B细胞基因表达级联的信息，以及蛋白质的全面调查 相互作用和集中的分子实验，以创建一个集成的，系统级的计算 Ahr和B细胞分化信号网络的模型。通过这些具体目标，我们将制定一个 系统水平的方法将提供对细胞信号传导的定量和机制性理解 在Ahr激动剂抑制B细胞分化中所涉及的网络。具体而言，基因组工具将 提供B细胞中基因之间的转录反应和功能关系的快照 分化途径，而计算建模将用于提供定量的生物 信令网络的结构。制定一个系统的方法对 环境卫生界作为一个整体，提供了一个机制，系统地调查 包含在改变的基因列表中的因果关系和改变基因的潜在逻辑。 在环境相关剂量下参与产生毒理学效应的信号网络。

A comprehensive evaluation of human exposure pathways at Superfund sites reveals that contaminants functioning as Ahr agonists present a significant risk to surrounding residents and immunological effects are one of the least studied toxciological end points. The primary objectives of this project are two-fold: (1) dissect the gene expression cascade involved in suppression of B-cell activation and IgM secretion following exposure to Ahr agonists; (2) combine information on the gene expression cascade with a comprehensive survey of protein interactions and focused molecular experimentation to create an integrated, systems-level model of the role of Ahr in the B-cell differentiation signaling network. We hypothesize that multiple nodes in the B-cell differentiation network are regulated by the Ahr. By dissecting the interrelationships within the gene expression cascade together with a comprehensive protein interaction map, we will be able to mechanistically model the dose-response behavior for Ahr B-cell immunotoxicity. This hypothesis will be tested using a unique combination of genomic and computational tools that dissect the transcriptional cascades following exposure to an Ahr agonist and infer the corresponding structure of the cellular signaling network for computational modeling. The specific aims of this proposal are: (1) identify Ahr-dependent alterations in the B-cell gene expression cascade following activation with LPS and exposure to the prototype Ahr agonist TCDD; (2) characterize the direct, cis-acting effects of Ahr activation on primary changes in gene expression in the B-cell differentiation cascade; (3) delineate the interrelationships between primary gene expression events and secondary and tertiary gene expression changes for Ahr-mediated alterations in B-cell differentiation; and (4) combine information on the Ahr-regulated B-cell gene expression cascade with a comprehensive survey of protein interactions and focused molecular experimentation to create an integrated, systems-level computational model of the Ahr and B-cell differentiation signaling network. Through these specific aims, we will develop a systems-level approach will provide a quantitative and mechanistic understanding of the cellular signaling network involved in the suppression of B-cell differentiation by Ahr agonists. Specifically, genomic tools will provide snapshots into transcriptional responses and functional relationships between genes in the B-cell differentiation pathway, while computational modeling will be used to provide a quantitative biological structure to the signaling network. The development of a systems approach is significant for the environmental health community as a whole by providing a mechanism to systematically investigate the cause-and-effect relationships contained within the lists of altered genes and the underlying logic of the signaling network involved in producing the toxicological effect at environmentally relevant doses.