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

剖析 Ah 受体介导的 B 细胞毒性的信号网络

• 批准号: 7466399
• 负责人: Russell S Thomas
• 金额: $ 28.52万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7466399
• 关键词: Agonist; Antigens; Aryl Hydrocarbon Receptor; B Cell Proliferation; B cell differentiation; B-Cell Activation; B-Lymphocytes; Behavior; Binding Sites; Bioinformatics; Biological; Cell Line; Cells; Cellular Structures; Combined Modality Therapy; Communities; Complex; Computer Simulation; Consensus; Data; Development; Dioxins; Dose; Elements; End Point; Enhancers; Environmental Health; Environmental Pollution; Evaluation; Event; Excision; Exposure to; Frequencies; Gene Expression; Genes; Genetic Transcription; Genome; Genomics; Hazardous Substances; Health; Immune response; Immunoglobulin M; Immunosuppression; Individual; J-Chain Immunoglobulins; Laboratories; Light; Lipopolysaccharides; Logic; Measurement; Mediating; Modeling; Molecular; Mus; Nuclear; Nucleic Acid Regulatory Sequences; Pathway interactions; Play; Poison; Positioning Attribute; Principal Investigator; Process; Production; Protein Interaction Mapping; Protein-Protein Interaction Map; Proteins; Publishing; Regulator Genes; Response Elements; Reverse Transcriptase Polymerase Chain Reaction; Risk; Role; Signal Transduction; Small RNA; Structure; Surveys; System; Testing; Tetrachlorodibenzodioxin; Therapeutic immunosuppression; Time; Toxic effect; Transcript; Transcriptional Regulation; aryl hydrocarbon receptor ligand; base; cell dedifferentiation; computational network modeling; computerized tools; design; disease registry; exposed human population; immunotoxicity; in vivo; innovation; macromolecule; prevent; programs; prototype; receptor; response; role model; superfund site; tool; 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.

对超级基金地点人类接触途径的综合评估表明，污染物 作为 Ahr 激动剂，对周围居民构成重大风险，并且免疫效应 研究最少的毒理学终点之一。该项目的主要目标有两个：(1) 剖析参与抑制 B 细胞活化和 IgM 分泌的基因表达级联 暴露于 Ahr 激动剂； (2) 将基因表达级联信息与综合信息相结合 对蛋白质相互作用的调查和重点分子实验，以创建 Ahr 在 B 细胞中的作用的集成系统级模型 分化信号网络。我们假设 B 细胞分化网络中的多个节点 受 Ahr 监管。通过一起剖析​​基因表达级联内的相互关系 有了全面的蛋白质相互作用图，我们将能够机械地模拟剂量反应 Ahr B 细胞免疫毒性行为。该假设将使用独特的组合进行测试 基因组和计算工具可剖析暴露于 Ahr 后的转录级联 激动剂并推断细胞信号网络的相应结构以进行计算建模。 该提案的具体目标是：(1) 识别 B 细胞基因表达中 Ahr 依赖性的改变 用 LPS 激活并暴露于原型 Ahr 激动剂 TCDD 后发生级联； (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 级联; (3) 描绘初级基因表达事件与次级和次要基因表达事件之间的相互关系 Ahr 介导的 B 细胞分化改变的三级基因表达变化； (4) 结合 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，以创建集成的系统级计算 Ahr 和 B 细胞分化信号网络模型。通过这些具体目标，我们将制定 系统级方法将提供对细胞信号传导的定量和机制理解 网络参与 Ahr 激动剂抑制 B 细胞分化。具体来说，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，而计算模型将用于提供定量的生物学 信令网络的结构。系统方法的开发对于 环境卫生界作为一个整体，提供一个机制来系统地调查 改变基因列表中包含的因果关系以及潜在的逻辑 信号网络参与在环境相关剂量下产生毒理学效应。