Elucidation of molecular mechanisms and functional significance of cooperation between glucocorticoid receptor and NF-kB in the airways

阐明气道中糖皮质激素受体与 NF-kB 合作的分子机制和功能意义

• 批准号: 9259045
• 负责人: Vineela Kadiyala
• 金额: $ 5.92万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2020-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9259045
• 关键词: Adrenal Cortex Hormones; Adverse effects; Allergens; American; Anti-Inflammatory Agents; Anti-inflammatory; Asthma; Attenuated; Binding; Binding Sites; Biological Assay; Cell Nucleus; Cells; ChIP-seq; Chromatin; Chromatin Loop; Chronic; Chronic Obstructive Airway Disease; Chymase; Clinic; Clustered Regularly Interspaced Short Palindromic Repeats; Cytokine Suppression; DNA Sequence; Data; Disease; Drug Design; Elements; Enhancers; Enzyme-Linked Immunosorbent Assay; Epithelial Cells; Extrinsic asthma; Feedback; Gene Activation; Gene Expression; Gene Targeting; Genes; Genetic Transcription; Glucocorticoid Receptor; Glucocorticoids; Goals; Imagery; Infection; Inflammatory; Intranasal Administration; Light; Liquid substance; Lung; Manuscripts; Mediating; Microscopic; Modeling; Molecular; Mucins; Mus; NF-kappa B; Nuclear Receptors; Pathway interactions; Patients; Pharmaceutical Preparations; Property; Protease Inhibitor; Proteins; Quantitative Reverse Transcriptase PCR; Reporter; Repression; Role; Site-Directed Mutagenesis; Staining method; Stains; Structure of parenchyma of lung; Techniques; Testing; Therapeutic; Treatment Efficacy; Western Blotting; Work; airway epithelium; airway hyperresponsiveness; airway inflammation; airway remodeling; allergic airway disease; allergic airway inflammation; base; cell type; chromosome conformation capture; cytokine; genome-wide analysis; glucocorticoid receptor alpha; glucocorticoid-induced orphan receptor; improved; in vivo; inflammatory marker; methacholine; mouse model; new therapeutic target; novel; novel therapeutics; overexpression; promoter; receptor binding; steroid hormone; transcription factor

Abstract Corticosteroids or glucocorticoids (GCs) are widely used to treat inflammatory airway diseases such as asthma. Despite their widespread use in the clinic, the molecular mechanisms underlying the therapeutic actions of GCs remain incompletely understood. Glucocorticoids mediate their actions by binding to the glucocorticoid receptor (GR) a nuclear receptor, which then translocates to the nucleus and regulates gene expression. Anti-inflammatory actions of GR have classically been attributed to GR binding to other transcription factors such as NF-KB and repressing their transcriptional activity while activation of gene expression by GR has been implicated in the side effects of GCs. Recent studies, however, have shown that GR can cooperate with NF-kB to activate gene expression. Indeed, our ChIP-Seq studies identified numerous genes that are regulated cooperatively by GR and NF-kB in the airway epithelium. In addition, some of these cooperatively activated genes have known anti-inflammatory actions that are glucocorticoid-independent. Based on this evidence, we hypothesize that GR and NF-kB cooperate to induce anti-inflammatory gene expression that contributes to therapeutic actions of GCs in airway epithelium. We will test our hypothesis by interrogating the mechanism of cooperation between GR and NF-kB to induce SERPINA3 and by elucidating the role of SERPINA3 in allergic airway inflammation. Our specific aims are 1) Identify and define the role of key DNA sequence elements mediating GR and NF-kB cooperation at a putative SERPINA3 enhancer and 2) Determine if SERPINA3 suppresses allergic airway inflammation in vivo. Through these aims we expect to demonstrate that GR and NFkB cooperation represents a novel pathway underpinning the therapeutic actions of GCs in inflammatory airway diseases.

摘要 皮质类固醇或糖皮质激素（GC）广泛用于治疗炎性气道疾病，例如 哮喘尽管它们在临床上广泛使用，但治疗性抗肿瘤的分子机制仍不清楚。 GC的作用仍然不完全清楚。糖皮质激素通过与糖皮质激素结合来介导其作用。 糖皮质激素受体（GR）是一种核受体，然后易位到细胞核并调节基因表达。 表情GR的抗炎作用经典地归因于GR与其他炎症因子的结合。 转录因子如NF-κ B，并在基因激活的同时抑制其转录活性 GR的表达与GC的副作用有关。然而，最近的研究表明， GR可与NF-κ B协同激活基因表达。事实上，我们的ChIP-Seq研究发现了许多 在气道上皮中由GR和NF-kB协同调节的基因。此外，其中一些 协同激活的基因具有已知的不依赖糖皮质激素的抗炎作用。 基于这些证据，我们推测GR和NF-κ B协同诱导抗炎基因表达， 在气道上皮中，GCs的表达有助于GCs的治疗作用。我们将测试我们的假设， 探讨GR和NF-κ B协同诱导SERPINA 3的机制， SERPINA 3在过敏性气道炎症中的作用我们的具体目标是：（1）确定和界定 在推定的SERPINA 3增强子处介导GR和NF-kB合作的关键DNA序列元件和2） 确定SERPINA 3是否抑制体内过敏性气道炎症。通过这些目标，我们希望 表明GR和NFkB的合作代表了支持治疗作用的新途径， GC在炎症性气道疾病中的作用