Dissecting the Signaling Network for Ah Receptor

剖析 Ah 受体的信号网络

• 批准号: 7064098
• 负责人: Russell S Thomas
• 金额: $ 31.27万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2011-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7064098
• 关键词: B lymphocyte; aromatic hydrocarbon receptor; benzofurans; biological signal transduction; carbopolycyclic compound; cell differentiation; cell line; computational biology; dioxins; environmental contamination; genetic regulation; genetic transcription; halobiphenyl /halotriphenyl compound; humoral immunity; immunoglobulin M; immunosuppression; immunotoxicity; laboratory mouse; leukocyte activation /transformation; lipopolysaccharides; lymphocyte proliferation; microarray technology; model design /development; molecular biology; protein protein interaction; protein structure function; recombinant DNA; transcription factor; B lymphocyte; aromatic hydrocarbon receptor; benzofurans; biological signal transduction; carbopolycyclic compound; cell differentiation; cell line; computational biology; dioxins; environmental contamination; genetic regulation; genetic transcription; halobiphenyl /halotriphenyl compound; humoral immunity; immunoglobulin M; immunosuppression; immunotoxicity; laboratory mouse; leukocyte activation /transformation; lipopolysaccharides; lymphocyte proliferation; microarray technology; model design /development; molecular biology; protein protein interaction; protein structure function; recombinant DNA; transcription factor

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.

对超级基金站点的人类暴露途径的全面评估揭示了污染物 作为AHR激动剂的作用，对周围居民带来了重大风险，免疫学影响是 研究最少的毒理学终点之一。该项目的主要目标是两个方面：（1） 剖析与B细胞激活抑制和IgM分泌有关的基因表达级联 暴露于AHR激动剂； （2）将有关基因表达级联的信息与全面的信息结合在一起 调查蛋白质相互作用和集中的分子实验，以创建AHR在B细胞中作用的集成的系统级模型 分化信号网络。我们假设B细胞分化网络中的多个节点 由AHR监管。通过解剖基因表达级联中的相互关系在一起 使用全面的蛋白质相互作用图，我们将能够机械地对剂量反应建模 AHR B细胞免疫毒性的行为。该假设将通过独特的组合进行检验 暴露于AHR后剖析转录级联的基因组和计算工具 激动剂和推断用于计算建模的细胞信号网络的相应结构。 该提案的具体目的是：（1）确定B细胞基因表达中AHR依赖性的变化 激活LPS并暴露于原型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主要变化的直接，顺式作用作用 级联; （3）描述主要基因表达事件与次级和次级和 AHR介导的B细胞分化改变的三级基因表达变化； （4）组合 有关AHR调节的B细胞基因表达级联的信息，并对蛋白质进行了全面调查 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，我们将开发一个 系统级方法将对细胞信号传导提供定量和机械理解 AHR激动剂抑制B细胞分化的网络。具体而言，基因组工具将 在B细胞中基因之间的转录响应和功能关系中提供快照 分化途径，而计算建模将用于提供定量生物学 信号网络的结构。系统方法的发展对于 环境卫生社区整体通过提供系统调查的机制 改变基因列表中包含的因果关系和该关系的基本逻辑 信号网络涉及在环境相关剂量下产生毒理学效应。