Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease

纤维化肺病中肌成纤维细胞的治疗靶向

• 批准号: 10218247
• 负责人: Victor J. Thannickal
• 金额: $ 149.99万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-16 至 2023-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10218247
• 关键词: Address; Alabama; Alveolar Macrophages; Animals; Apoptosis; Apoptotic; Asthma; Autoantibodies; B-Lymphocytes; Biogenesis; Biological Markers; Biology; Biostatistics Core; Cells; Chronic Obstructive Airway Disease; Clinical; Clinical Trials; Complex; Data; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Enzymes; Epigenetic Process; Fibroblasts; Fibrosis; Future; Genes; Goals; Growth Factor; Immune; Link; Lung diseases; Measures; Mediator of activation protein; Metabolic; Metabolic Control; Metabolism; Mitochondria; Myofibroblast; NADPH Oxidase; Natural regeneration; Oxidation-Reduction; Oxidative Stress; Pathogenesis; Pharmaceutical Preparations; Pharmacotherapy; Phase; Phase III Clinical Trials; Phenotype; Physiological; Plasma; Pleura; Population; Process; Program Research Project Grants; Pulmonary Fibrosis; Pulmonary Hypertension; Reactive Oxygen Species; Regulation; Research Personnel; Resistance; Role; Safety; Signal Pathway; Signal Transduction; Syndrome; Testing; Tissues; Universities; Work; adaptive immunity; base; cell type; epigenetic regulation; human subject; idiopathic pulmonary fibrosis; immunoregulation; improved; inhibitor/antagonist; lung injury; macrophage; migration; novel; novel therapeutic intervention; primary endpoint; programs; response; safety testing; secondary endpoint; small molecule inhibitor; targeted treatment; therapeutic target

PROJECT SUMMARY Fibrosis involving the airways, vasculature, alveoli, and pleura is seen, to varying degrees, in a number of clinical syndromes, including asthma, subphenotypes of chronic obstructive pulmonary disease, pulmonary hypertension, and idiopathic pulmonary fibrosis (IPF). IPF is the most enigmatic and fatal of the fibrotic lung disorders. Despite the recent approval of two drugs, survival has not significantly improved. Pulmonary fibrosis represents a complex tissue response to lung injury that involves a number of cell types, mediators, and signaling pathways. In just over the last few years, several new concepts in disease pathogenesis have emerged; these include metabolic reprogramming, epigenetics, immune modulation, macrophage biology and the invasive/apoptosis-resistant phenotype of myofibroblasts (myoFbs). Each of these concepts/paradigms is addressed in this renewal application of this tPPG. Work conducted during Cycle I of this tPPG has validated the pro-fibrotic effects of the reactive oxygen species (ROS)-regenerating enzyme, NADPH oxidase 4 (NOX4), and identified circulating plasma biomarkers of oxidative stress in human subjects with IPF. In Project 1, we will conduct a Phase IIb clinical trial of the safety and efficacy of a NOX1/4 inhibitor in IPF using multiple biomarkers and physiologic measures as primary and secondary end-points. Project 2 will test the hypothesis that redox-metabolic reprogramming of myoFbs accounts for the observed pro-fibrotic effects of NOX4. Based on emerging data on macrophage-myoFb interactions in fibrosis, Project 3 will test the hypothesis that NOX4 modulates macrophage mitochondrial ROS and metabolism to polarize alveolar macrophages to a pro-fibrotic phenotype. Project 4 will test the novel hypothesis that B-cell derived autoantibodies epigenetically reprogram Fbs to an anti-apoptotic phenotype. Together, this tPPG will elucidate critical links between cellular redox control and metabolic reprogramming, uncover novel regulatory mechanisms of macrophage polarization, and illuminate previously unrecognized connections between innate/adaptive immunity, epigenetics and lung fibrosis. Importantly, this tPPG will advance a novel anti-fibrotic drug therapy that more specifically targets redox biology in IPF, which will enable future Phase III clinical trials.

项目总结 不同程度的纤维化累及呼吸道、血管、肺泡和胸膜。 临床症状，包括哮喘、慢性阻塞性肺疾病的亚型、肺 高血压和特发性肺纤维化(IPF)。肺间质纤维化是纤维化肺中最神秘和最致命的。 精神错乱。尽管最近批准了两种药物，但存活率并没有显著提高。肺 纤维化是对肺损伤的一种复杂的组织反应，涉及多种细胞类型、介质、 和信号通路。在过去的几年里，疾病发病机制中的几个新概念 包括代谢重新编程、表观遗传学、免疫调节、巨噬细胞生物学和 肌成纤维细胞(MyoFbs)的侵袭/抗凋亡表型。这些概念/范例中的每个都是 已在此tPPG的续订申请中解决。在本TPPG第一周期期间进行的工作已得到验证 活性氧(ROS)再生酶NADPH氧化酶4(NOX4)的促纤维化作用 并确定了IPF受试者氧化应激的循环血浆生物标记物。在项目1中，我们 将对一种NOX1/4抑制剂在IPF中的安全性和有效性进行IIb期临床试验，使用多个 生物标志物和生理指标作为主要和次要终点。项目2将检验这一假设 对myoFbs的氧化还原代谢重编程解释了观察到的NOX4的促纤维化作用。基座 根据纤维化中巨噬细胞-myoFb相互作用的新数据，项目3将检验NOX4的假设 调节巨噬细胞线粒体ROS和代谢，使肺泡巨噬细胞极化为促纤维化 表型。项目4将测试新的假设，即B细胞衍生的自身抗体在表观上重新编程 FBS转化为抗细胞凋亡表型。总之，这一tPPG将阐明细胞氧化还原之间的关键联系 控制和代谢重新编程，发现巨噬细胞极化的新调节机制，以及 阐明先天/获得性免疫、表观遗传学和肺之间以前未知的联系 纤维化症。重要的是，这种tPPG将推进一种新的抗纤维化药物治疗，更有针对性地针对 IPF中的氧化还原生物学，这将使未来的第三阶段临床试验成为可能。