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: 8735177
• 负责人: Victor J. Thannickal
• 金额: $ 191.72万
• 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 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735177
• 关键词: Accounting; Actins; Address; Alabama; Alveolar; Alveolus; Animal Model; Apoptosis; Asthma; Behavior; Cell Adhesion; Cells; Characteristics; Chronic Obstructive Airway Disease; Clinical; Clinical Data; Clinical Trials; Complex; Contracts; Development; Disease; Effector Cell; Enzymes; Epithelial Cells; Experimental Animal Model; Extracellular Matrix Proteins; Fibroblasts; Fibrosis; Gene Expression; Goals; Hamman-Rich syndrome; Human Resources; Injury; Integrins; Interest Group; Joints; Lead; Lung; Lung diseases; MADH2 gene; Maintenance; Mediator of activation protein; Mesenchymal; MicroRNAs; Molecular Target; Myofibroblast; Myosin ATPase; NADPH Oxidase; Nephroblastoma; Oxidants; Oxidative Stress; Pathogenesis; Pathway interactions; Patients; Pharmaceutical Preparations; Phase; Phenotype; Pleura; Pleural Mesothelial Cell; Population; Process; Production; Program Research Project Grants; Property; Proteins; Publications; Pulmonary Fibrosis; Pulmonary Hypertension; Reaction; Research Personnel; Resistance; Role; Signal Pathway; Signal Transduction; Stem cells; Stress Fibers; Syndrome; Testing; Therapeutic; Tissues; Treatment Efficacy; United States; United States Food and Drug Administration; Universities; base; cell type; epithelial to mesenchymal transition; extracellular; falls; human subject; meetings; migration; new therapeutic target; novel; pre-clinical; progenitor; programs; public health relevance; reconstitution; stem; therapeutic target; therapy development

DESCRIPTION (provided by applicant): 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). Currently, there are no FDA-approved anti-fibrotic therapies for any of these disorders in the United States. A common feature of fibrosis in these clinical-pathological contexts is the activation of tissue myofibroblasts. In this translational Program Project Grant (tPPG) application, we propose to develop pharmacologic strategies and agents targeting the myofibroblast in the most enigmatic and fatal form of pulmonary fibrosis, IPF. Current paradigms of the origin(s) of myofibroblasts posit that these fibrogenic cells derive from resident mesenchymal progenitors, alveolar epithelial cells (via epithelial-to-mesenchymal transition), or circulating fibrocytes. In this tPPG, we will investigate the role of pleural mesothelial cells (PMCs) as progenitors of activated lung myofibroblasts (Project 1). While myofibroblasts are widely considered a specific subset of a heterogeneous fibroblast population, in reality, they themselves manifest a number of different phenotypes, including migration/invasion, proliferation, contractility and apoptosis-resistance. Maintenance of myofibroblast differentiation and activation is governed by extracellular factors (matrix stiffness activation of latent TGF-¿), cell adhesion/contractile factors (integrins, RhoA), and intracellular signaling cascades (SMAD2/3, Wilm's tumor-1) that activate or repress fibrogenic gene expression. These interacting pathways are controlled by the anti-fibrotic micro-RNA, miR-31, and the pro-fibrotic oxidant-generating enzyme, NADPH oxidase-4 (NOX4). This tPPG will establish proof-of-concept and provide essential pre-clinical data supporting the therapeutic efficacy of reconstituting miR-31 and/or inhibiting the expression/activation of N0X4 in experimental animal models and in cell/tissues of patients with IPF, leading rapidly to Phase l/ll clinical trials for this recalcitrant lung disease.

描述（由申请人提供）：涉及气道、脉管系统、肺泡和胸膜的纤维化不同程度地见于许多临床综合征，包括哮喘、慢性阻塞性肺病的亚表型、肺动脉高压和特发性肺纤维化（IPF）。目前，美国还没有 FDA 批准的针对这些疾病的抗纤维化疗法。这些临床病理背景下纤维化的一个共同特征是组织肌成纤维细胞的激活。在这项转化计划项目拨款（tPPG）申请中，我们建议开发针对最神秘和致命的肺纤维化（IPF）中的肌成纤维细胞的药理学策略和药物。目前关于肌成纤维细胞起源的范式认为，这些成纤维细胞源自常驻间充质祖细胞、肺泡上皮细胞（通过上皮间质转化）或循环纤维细胞。在此 tPPG 中，我们将研究胸膜间皮细胞 (PMC) 作为活化肺肌成纤维细胞祖细胞的作用（项目 1）。虽然肌成纤维细胞被广泛认为是异质成纤维细胞群的特定子集，但实际上，它们本身表现出许多不同的表型，包括迁移/侵袭、增殖、收缩性和抗凋亡性。肌成纤维细胞分化和激活的维持受细胞外因子（潜在 TGF-¿ 的基质硬度激活）、细胞粘附/收缩因子（整合素、RhoA）和细胞内因子的控制。 激活或抑制纤维化基因表达的信号级联（SMAD2/3、维尔姆氏肿瘤-1）。这些相互作用的途径由抗纤维化的微小 RNA、miR-31 和促纤维化的氧化剂生成酶 NADPH 氧化酶 4 (NOX4) 控制。该 tPPG 将建立概念验证并提供必要的临床前数据，支持在实验动物模型和 IPF 患者的细胞/组织中重建 miR-31 和/或抑制 N0X4 表达/激活的治疗功效，从而迅速进入针对这种顽固性肺病的 I/II 期临床试验。