Airway Epithelial Cell Farnesoid X Receptor in COPD Pathophysiology

气道上皮细胞 Farnesoid X 受体在 COPD 病理生理学中的作用

• 批准号: 9770704
• 负责人: RAJU C REDDY
• 金额: $ 39.13万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9770704
• 关键词: Address; Adverse effects; Affect; Agonist; Alveolar; Anti-inflammatory; Automobile Driving; Binding; Blood Vessels; Cause of Death; Chronic; Chronic Obstructive Airway Disease; Consensus; Data; Development; Disease; Disease Progression; Disease model; Environmental and Occupational Exposure; Epithelial Cells; Exposure to; F-Box Proteins; Functional disorder; Goals; Human; In Vitro; Inflammation; Inflammation Mediators; Inflammatory Response; Inhalation; Isomerase; Knock-in; Knock-out; Ligands; Lung; Lung diseases; Mediating; Mediator of activation protein; Mus; Mutation; Nuclear Hormone Receptors; Nuclear Orphan Receptor; Oxidative Stress; Pathogenesis; Pathogenicity; Pathology; Patient-Focused Outcomes; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phosphotransferases; Production; Pulmonary Emphysema; Receptor Activation; Receptor Gene; Research; Respiratory physiology; Risk Factors; Role; Severities; Severity of illness; Site; Smoke; Smoking; Source; Testing; Therapeutic; Transfection; Transgenic Mice; Transgenic Organisms; Translational Research; Ubiquitination; Validation; airway obstruction; base; cigarette smoke; cigarette smoke-induced; cigarette smoke-induced COPD; cigarette smoke-induced inflammation; cigarette smoking; experience; improved; in vivo; knock-down; knockout gene; lung injury; new therapeutic target; novel; novel therapeutics; prevent; receptor; receptor binding; receptor downregulation; receptor expression; response; smoke-induced COPD; smoking cessation; toxicant; ubiquitin-protein ligase

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is the 3rd-leading cause of death in the US, generally due to cigarette smoking. Current treatments, including smoking cessation after the very earliest stages, provide only short-term benefit and cannot stop its inexorable progression. Novel therapies to halt progression are thus urgently needed. COPD pathophysiology includes bronchial inflammation and septal destruction leading to emphysema, with such septal destruction caused by inflammation-associated oxidative stress and protease secretion. Based on promising preliminary findings, the proposed research will test the beneficial role in COPD and mechanisms that regulate farnesoid X receptor (FXR), a nuclear hormone receptor whose roles in lungs and COPD are unknown. Preliminary studies revealed FXR is downregulated in airway epithelial cells (AECs) of COPD patients and in mice with cigarette smoke (CS)-induced COPD, and that CS elicits such FXR downregulation in vitro, leading us to hypothesize that FXR downregulation in patients contributes to COPD pathogenesis. We also found that FXR knockout (KO) exacerbates CS-induced inflammation and emphysematous lung damage in mice, whereas stimulating FXR by treating mice with FXR agonist during smoke exposure blocked these effects, suggesting FXR agonists may be useful for COPD therapy. Mechanistic studies of CS-induced FXR downregulation suggest it is mediated by ubiquitination and proteasomal degradation, triggered by binding of an E3-ligase containing a specific F-box protein. Further preliminary findings indicate that binding of an FXR agonist blocked this by promoting binding of the peptydylprolyl isomerase Pin1, because the F-box protein was unable to bind to the resulting cis-Pro form of FXR. Based on these novel findings, the specific aims are: 1: To determine whether the suppression of FXR activity that occurs in COPD promotes COPD progression and severity and the mechanisms driving such suppression; and 2: To test whether activating FXR, specifically in AECs or generally in lung, ameliorates COPD severity and progression and the mechanisms by which agonists block FXR degradation. To achieve these aims we will utilize novel transgenic mice in which FXR is deleted or constitutively active specifically in AECs and in vitro studies utilizing FXR or F-box protein constructs carrying mutations at sites believed to be crucial for their interaction. The results will determine the pathogenic role in COPD of a previously-overlooked receptor, and the opposing mechanisms by which CS promotes its degradation but agonists stabilize it. They may also identify FXR as a promising new therapeutic target for a widespread fatal disease.

项目总结 慢性阻塞性肺疾病(COPD)是美国第三大死亡原因，通常是由于 抽烟。目前的治疗方法，包括在最早的阶段戒烟，只能提供 这是一种短期利益，无法阻止其不可阻挡的发展。因此，阻止病情发展的新疗法 急需之物。COPD的病理生理包括支气管炎和间隔破坏，导致 肺气肿，这种间隔破坏是由炎症相关的氧化应激和蛋白酶引起的 分泌物。基于有希望的初步发现，这项拟议的研究将测试对COPD的有益作用 以及调节法尼类X受体(FXR)的机制，FXR是一种核激素受体，其在肺中的作用 和慢性阻塞性肺病是未知的。初步研究表明，FXR在呼吸道上皮细胞(AECs)中下调 在COPD患者和香烟烟雾(CS)诱导的COPD小鼠中，CS引起这种FXR 体外下调，导致我们假设患者的FXR下调与COPD有关 发病机制。我们还发现，FXR基因敲除(KO)加剧了CS诱导的炎症和 小鼠肺气肿肺损伤，而FXR激动剂治疗小鼠则刺激FXR 烟雾暴露可阻断这些效应，提示FXR激动剂可能对COPD治疗有用。 CS诱导FXR下调的机制研究表明，它是由泛素化和 蛋白酶体降解，由包含特定F-box蛋白的E3-连接酶结合而触发。进一步 初步研究结果表明，FXR激动剂的结合通过促进 由于F-box蛋白不能与所产生的顺式-Pro形式的 FXR。基于这些新的发现，具体目的是：1：确定FXR的抑制是否 COPD患者的活动促进COPD的进展和严重程度及其机制 抑制；和2：测试激活FXR，特别是在AECs或一般在肺内，是否可以改善 COPD的严重程度和进展，以及激动剂阻止FXR降解的机制。要实现 为了达到这些目的，我们将利用新型转基因小鼠，在这些小鼠中，FXR被特异性地缺失或具有结构性活性 AECS和利用FXR或F-box蛋白构建的体外研究携带突变的位点据信是 对他们的互动至关重要。这一结果将确定一种以前被忽视的COPD的致病作用 受体，以及CS促进其降解但激动剂稳定它的相反机制。他们 也可能将FXR确定为一种广泛的致命疾病的有前途的新治疗靶点。