Characterization of the Pathways Linking Ah Receptor

连接 Ah 受体途径的表征

• 批准号: 7064096
• 负责人: Norbert E Kaminski
• 金额: $ 29.75万
• 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/7064096
• 关键词: B lymphocyte; DNA methylation; aromatic hydrocarbon receptor; benzofurans; binding proteins; biological signal transduction; carbopolycyclic compound; cell differentiation; cell growth regulation; computational biology; cytokine receptors; dioxins; environmental contamination; gene expression; halobiphenyl /halotriphenyl compound; humoral immunity; immune response; immunofluorescence technique; immunomagnetic separation; immunosuppression; interferon gamma; laboratory mouse; microarray technology; model design /development; molecular biology; polymerase chain reaction; transcription factor; western blottings

The overall goal of this 5 year research plan is two-fold: (a) to characterize the molecular mechanism for impairment of B cell differentiation by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and dioxin-like compounds; and (b) to develop a computational model describing the biochemical pathways that regulate B cell differentiation and the interaction of this pathway with the aryl hydrocarbon reception (AhR). Previous studies have established the B cell as a sensitive cellular target for TCDD as evidenced by suppression of immunoglobulin (lg)M through a direct effect on B cells involving the AhR. Moreover, suppression of the IgM response by TCDD is mediated at the level of transcription and, in part, occurs through AhR binding to dioxin response elements (ORE) in regulatory domains within the Ig heavy chain (IgH) 3'a enhancer. Importantly, in addition to IgH suppression, the Ig kappa light chain (Igk), IgM joining chain (J chain) and X-box protein-1 (XBP-1), which are essential for IgM assembly and secretion, are also markedly suppressed by TCDD suggesting the involvement of additional targets other than just the IgH 3'a enhancer. Moreover, TCDD alters the levels of B lymphocyte.-induced maturation protein-1 (Blimp-1), a master regulatory of B cell differentiation and its downstream target, Pax5, a transcriptional represser of B cell differentiation, which represses IgH, Igk, J chain and XBP-1. We also show that TCDD treatment of B cells: (a) altered the magnitude of DNA methylation and MRNA levels of DNA methylating enzymes, Dnmt3b, which putatively influences the expression of genes crucial to B cell differentiation, including Pax5; (b) is functionally antagonized by IFNg; and (c) rapidly induces the suppressor of cytokine signaling-2 (SOCS-2), a protein that negatively regulates signaling through cytokine receptors coupled to the JAK/STAT pathway, such as the IFNg receptor (IFNgR). The project objective is to test the hypothesis: Suppression of the primary humoral immune response by AhR agonists is mediated through changes in the B cell differentiation program via a mechanism that is blocked by IFNg. A computational description of the biochemical pathway of B cell differentiation and the direct interactions of AhR agonists on this pathway, will provide a mechanistic approach for predicting the effects of AhR agonists, alone and in combination as complex mixtures, on the pathway and on humoral immune responses.

该5年研究计划的总体目标是两个方面：（a）表征分子机制 B细胞分化的损害受2,3,7,8-四氯迪本佐-P-二恶英（TCDD）和二恶英的损害 化合物； （b）开发一个描述调节b的生化途径的计算模型 细胞分化以及该途径与芳基烃接收（AHR）的相互作用。以前的 研究已经确定了B细胞为TCDD的敏感细胞靶标的 免疫球蛋白（LG）M通过涉及AHR的B细胞的直接作用。而且，抑制IgM TCDD的响应是在转录水平上介导的，部分是通过AHR与二恶英结合发生的 Ig重链（IGH）3'a增强子内的调节域中的响应元素（矿石）。重要的是， 除了IG抑制外，IG Kappa轻链（IGK），IGM连接链（J链）和X-box Protein-1-1 （XBP-1）对于IGM组装和分泌至关重要，也被TCDD明显抑制 暗示除了IGH 3'a增强子外，其他目标的参与。此外，TCDD 改变B淋巴细胞诱导的成熟蛋白-1（Blimp-1）的水平，B细胞的主要调节 分化及其下游靶标Pax5，B细胞分化的转录阻遏物 压抑IGH，IGK，J链和XBP-1。我们还表明了TCDD对B细胞的处理：（a）改变了 DNA甲基化和mRNA水平的DNA甲基化酶，DNMT3B的大小，该甲基化酶的大小 影响基因对B细胞分化至关重要的基因的表达，包括PAX5； （b）在功能上 由IFNG对抗； （c）迅速诱导细胞因子信号传导-2（SOCS-2）的抑制剂，蛋白 通过耦合到jak/stat途径的细胞因子受体对信号进行负调节，例如 IFNG受体（IFNGR）。项目目标是检验假设：抑制主要 AHR激动剂的体液免疫反应是通过B细胞分化的变化来介导的 通过IFNG阻止的机制进行程序。生化途径的计算描述 B细胞分化和AHR激动剂在此途径上的直接相互作用将提供机械 单独和作为复杂混合物组合的AHR激动剂对AHR激动剂的影响的方法， 途径和体液免疫反应。