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: 9980973
• 负责人: Victor J. Thannickal
• 金额: $ 53.23万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 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 2020-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980973
• 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 therapeutics; 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.

项目摘要 在多个程度上看到涉及气道，脉管系统，肺泡和胸膜的纤维化。 临床综合征，包括哮喘，慢性阻塞性肺疾病的亚表征 高血压和特发性肺纤维化（IPF）。 IPF是纤维化肺最神秘和致命的 疾病。尽管最近获得了两种药物的批准，但生存并未显着改善。肺 纤维化代表对肺损伤的复杂组织反应，涉及多种细胞类型，介体， 和信号通路。在过去的几年中，疾病发病机理上的几个新概念已有 出现；这些包括代谢重编程，表观遗传学，免疫调节，巨噬细胞生物学和 肌纤维细胞（MyOFB）的侵入性/凋亡耐药表型。这些概念/范式中的每一个都是 在此TPPG的此更新应用中解决。该TPPG周期I期间进行的工作已验证 活性氧（ROS）再生酶的促纤维化作用，NADPH氧化酶4（NOX4）， 并确定了IPF人类受试者中氧化应激的循环血浆生物标志物。在项目1中，我们 将对IPF中NOX1/4抑制剂的安全性和功效进行IIB期临床试验。 生物标志物和生理措施作为主要和次要终点。项目2将检验假设 MyOFB的氧化还原代谢重编程解释了NOX4的促纤维化作用。基于 在纤维化中巨噬细胞 - 摩诺夫相互作用的新兴数据上，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纤维化 表型。项目4将测试B细胞衍生的自身抗体表观遗传学的新假设 FBS到抗凋亡表型。总之，该TPPG将阐明细胞氧化还原之间的关键联系 控制和代谢重编程，发现巨噬细胞极化的新型调节机制， 阐明先前无法识别的先天/适应性免疫，表观遗传学和肺 纤维化。重要的是，该TPPG将推进一种新型的抗纤维化药物疗法，更具体地针对 IPF中的氧化还原生物学将使未来的III期临床试验。