Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease

描述(申请人提供)：涉及呼吸道、血管、肺泡和胸膜的纤维化可不同程度地出现在许多临床症状中，包括哮喘、慢性阻塞性肺疾病的亚型、肺高压和特发性肺纤维化(IPF)。目前，在美国还没有FDA批准的抗纤维化疗法来治疗这些疾病。在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。在这个翻译计划项目拨款(TPPG)的应用中，我们建议开发针对肺纤维化中最神秘和最致命的形式的肌成纤维细胞的药物策略和药物。目前的肌成纤维细胞起源范式(S)认为，这些成纤维细胞来源于常驻的间充质前体细胞、肺泡上皮细胞(通过上皮向间充质转化)或循环中的纤维细胞。在本研究中，我们将研究胸膜间皮细胞(PMC)作为活化的肺肌纤维母细胞的前体细胞的作用(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体中的一个特殊亚群，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、收缩和抗凋亡。肌成纤维细胞分化和激活的维持受细胞外因子(基质刚性潜伏的转化生长因子β的激活)、细胞黏附/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通路(Smad2/3，Wilm‘s Tumor-1)。这些相互作用的途径由抗纤维化的微型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基本的临床前数据，支持在实验动物模型和IPF患者的细胞/组织中重组MIR-31和/或抑制N0X4的表达/激活的治疗效果，从而迅速启动这种顽固性肺部疾病的L/11期临床试验。

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.