An Endogenous Ah Receptor Ligand: Gene and Physiological Responses

内源性 Ah 受体配体：基因和生理反应

• 批准号: 7487558
• 负责人: Thomas A Gasiewicz
• 金额: $ 22.64万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-22 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7487558
• 关键词: Agonist; Allergic; Aryl Hydrocarbon Receptor; Asthma; Biological; Carboxylic Acids; Cardiovascular Diseases; Cells; Chronic Obstructive Airway Disease; Data; Defect; Development; Disease; Dose; Environment; Esters; Evolution; Family member; Family suidae; Fibrinogen; Fibroblasts; Genes; Goals; Human; Hypertension; Indoles; Inflammation; Inflammatory; Inflammatory Response; Lead; Ligands; Lung; Lung Inflammation; Malignant Neoplasms; Molecular; Mus; Pathogenesis; Physiological; Process; Protein Family; Regulation; Role; Signal Pathway; Signal Transduction; Structure; Tetrachlorodibenzodioxin; Therapeutic Intervention; Thiazoles; Tissues; Toxic effect; Work; activating transcription factor; aryl hydrocarbon receptor ligand; base; body system; indole; mouse model; novel; pre-clinical; receptor; response

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.

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之一。该家族的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保守，并且缺乏 AhR 的小鼠在多个器官系统中表现出许多缺陷，但其正常功能尚不清楚。最近的工作从猪肺中鉴定出一种内源性配体 2-(1'H-吲哚-3'-羰基)-噻唑-4-羧酸甲酯 (ITE)，并证明其是一种有效的 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 的相互作用存在差异，因此暴露会导致不同的分子和生物学后果。还假设，基于表明 AhR 在炎症调节中的作用的研究，ITE 可能作为肺部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肺部炎症的临床前小鼠模型，我们还将确定在 ITE、TCDD 或已知的 AhR 拮抗剂存在的情况下炎症反应是否相似或不同，并将开始表征可能决定这些相似性或差异的细胞和信号传导途径。鉴于大量数据表明炎症在慢性阻塞性肺病、高血压、心血管疾病、哮喘等过敏性疾病和癌症等多种疾病的发病机制中的作用，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。