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: 7293745
• 负责人: Thomas A Gasiewicz
• 金额: $ 19.25万
• 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/7293745
• 关键词: Address; Agonist; Alleles; Allergic; Aryl Hydrocarbon Receptor; Asthma; Autoimmune Process; Binding; Biological; Biological Process; Carboxylic Acids; Cardiovascular Diseases; Cells; Chronic Obstructive Airway Disease; Circadian Rhythms; Data; Defect; Development; Dioxins; Disease; Dose; Endotoxins; Environment; Environmental Pollution; Esters; Evolution; Exposure to; Family member; Family suidae; Fetus; Fibrinogen; Fibroblasts; Gene Expression; Genes; Goals; Helix-Turn-Helix Motifs; Human; Hypertension; Indoles; Inflammation; Inflammatory; Inflammatory Response; Lead; Ligands; Lung; Lung Inflammation; Malignant Neoplasms; Molecular; Mus; Oxygen measurement, partial pressure, arterial; Pathogenesis; Pattern; Physiological; Play; Process; Protein Family; Proteins; Regulation; Research Personnel; Role; Signal Pathway; Signal Transduction; Stimulus; Structure; Testing; Tetrachlorodibenzodioxin; Therapeutic Intervention; Thiazoles; Tissues; Toxic effect; Work; activating transcription factor; aryl hydrocarbon receptor ligand; base; body system; indole; mouse Ahr protein; mouse model; novel; pre-clinical; receptor; receptor function; response; single-minded protein

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）：芳基烃受体（AHR）是配体激活的转录因子，也是包含BHLH-PAS结构域结构的蛋白质家族之一。这个家庭的成员参与了组织环境中的信号的反应，并在发育和细胞分化中起着调节作用。尽管AHR在整个进化过程中都得到了保守，并且缺乏AHR的小鼠在几个器官系统中显示出许多缺陷，但其正常功能尚不清楚。最近的工作已经从猪肺中鉴定出一种内源性配体2-（1'H-indole-3'-羰基） - 硫唑-4-羧酸甲酯（ITE），并证明这是有效的AHR激动剂。但是，与有毒的AHR配体（例如2,3,7,8-四氯迪本佐-P-二恶英（TCDD）），即使在非常高剂量的情况下，ITE也会在小鼠中产生毒性。假设ITE与有毒配体相比与AHR差异相互作用，从而导致不同的分子和生物学后果。还可以假设，基于表明AHR在调节炎症中的作用的工作，ITE可能具有新颖的作用，作为肺部炎症过程的调节分子。使用原代小鼠和人肺成纤维细胞，我们将通过微阵列分析，ITE和TCDD引起的基因谱的差异和/或相似性来严格确定。使用分离的肺细胞和肺部炎症的临床前小鼠模型，我们还将在ITE，TCDD或已知的AHR拮抗剂的存在下确定炎症反应是相似的还是不同的，并将开始表征可以确定这些相似性或差异的细胞和信号传导途径。考虑到大量数据表明炎症在多种疾病的发病机理中的作用，包括慢性阻塞性肺部疾病，高血压，心血管疾病，哮喘和癌症等多种疾病的发病机理中的作用，这些研究的目标特别重要。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措施。