An Endogenous Ah Receptor Ligand: Gene and Physiological Responses

描述（由申请人提供）：芳烃受体（AhR）是一种配体激活的转录因子，是含有bHLH-PAS结构域结构的蛋白质家族中的一员。该家族成员参与响应组织环境中的信号，并在发育和细胞分化中发挥调节作用。尽管AhR在整个进化过程中一直被保守，缺乏AhR的小鼠在几个器官系统中表现出许多缺陷，但其正常功能尚不清楚。最近的工作已经从猪肺中发现了一种内源性配体，2-（1' h -吲哚-3'-羰基）-噻唑-4-羧酸甲酯（ITE），并证明它是一种有效的AhR激动剂。然而，与有毒的AhR配体如2,3,7,8-四氯二苯并-对二恶英（TCDD）不同，ITE即使在非常高的剂量下也不会对小鼠产生毒性。据推测，与有毒配体相比，ITE与AhR的相互作用不同，因此暴露会导致不同的分子和生物学后果。也有人假设，基于表明AhR在炎症调节中的作用的研究，ITE可能作为肺炎症过程的调节分子具有新的作用。使用原代小鼠和人肺成纤维细胞，我们将通过微阵列分析严格确定ITE和TCDD诱导的基因谱的差异和/或相似性。使用分离的肺细胞和临床前小鼠肺炎症模型，我们还将确定炎症反应在ITE、TCDD或已知AhR拮抗剂存在时是否相似或不同，并将开始表征可能决定这些相似性或差异的细胞和信号通路。鉴于大量数据表明炎症在包括慢性阻塞性肺病、高血压、心血管疾病、哮喘等过敏性疾病和癌症在内的几种疾病的发病机制中所起的作用，这些研究的目标具有特别重要的意义。了解ITE和AhR在调节炎症过程中的作用可能会导致可能的治疗干预。

DESCRIPTION (provided by applicant): The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor and one of a family of proteins containing the bHLH-PAS domain structure. Members of this family are involved in responding to signals in the tissue environment and serve regulatory roles in development and cellular differentiation. Although the AhR has been conserved throughout evolution and mice lacking the AhR show many defects in several organ systems, its normal function is not known. Recent work has identified an endogenous ligand, 2-(1'H-indole-3'- carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE), from porcine lung and demonstrated this to be a potent AhR agonist. However, unlike toxic AhR ligands like 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), ITE produces no toxicity in mice even at very high doses. It is hypothesized that ITE differentially interacts with the AhR as compared to toxic ligands such that exposure results in different molecular and biological consequences. It is also hypothesized that, based on work indicating a role of the AhR in the regulation of inflammation, that ITE may have a novel role as a regulatory molecule for inflammatory processes in the lung. Using primary mouse and human lung fibroblasts, we will rigorously determine, by microarray analyses, differences and/or similarities in the gene profile induced by ITE and TCDD. Using both isolated lung cells and a pre-clinical mouse model of lung inflammation, we will also determine whether the inflammatory response is similar or different in the presence of ITE, TCDD, or known AhR antagonists, and will begin to characterize the cellular and signaling pathways that may determine these similarities or differences. The goals of these studies are of particular significance given the wealth of data indicating a role of inflammation in the pathogenesis of several diseases including chronic obstructive pulmonary disease, hypertension, cardiovascular disease, allergic diseases such as asthma, and cancer. Understanding the role of ITE and the AhR in modulating inflammatory processes may lead to possible therapeutic interventions.