Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease

描述（由申请人提供）：包括气道、脉管系统、肺泡和胸膜在内的纤维化在不同程度上见于许多临床综合征，包括哮喘、慢性阻塞性肺疾病亚表型、肺动脉高压和特发性肺纤维化（IPF）。目前，在美国还没有fda批准的针对这些疾病的抗纤维化疗法。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活化。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形式的肌成纤维细胞的药物策略和药物。目前关于肌成纤维细胞起源的观点认为，这些成纤维细胞来源于常驻间充质祖细胞、肺泡上皮细胞（通过上皮细胞向间充质细胞的转化）或循环纤维细胞。在这个tPPG中，我们将研究胸膜间皮细胞（PMCs）作为活化的肺肌成纤维细胞的祖细胞的作用（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体的一个特定子集，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。肌成纤维细胞分化和激活的维持受细胞外因子（基质刚度激活潜伏TGF-¿）、细胞粘附/收缩因子（整合素，RhoA）和细胞内因子的控制

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.