Therapeutic Targeting of the Myofibroblast in Fibrotic Lung Disease

描述（由申请人提供）：在许多临床综合征（包括哮喘、慢性阻塞性肺疾病的亚表型、肺动脉高压和特发性肺纤维化（IPF））中不同程度地观察到涉及气道、脉管系统、肺泡和胸膜的纤维化。目前，在美国没有FDA批准的抗纤维化疗法用于任何这些疾病。在这些临床病理学背景下纤维化的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资助（tPPG）申请中，我们建议开发针对最神秘和致命形式的肺纤维化IPF中的肌成纤维细胞的药理学策略和药物。肌成纤维细胞的起源的当前范例表明这些纤维发生细胞来源于常驻间充质祖细胞、肺泡上皮细胞（通过上皮向间充质转化）或循环纤维细胞。在本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体的特定子集，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活化的维持受细胞外因子（潜伏性TGF-β的基质硬度活化）、细胞粘附/收缩因子（整合素，RhoA）和细胞内因子（整合素，RhoA）控制。 信号级联（SMAD 2/3，Wilm's tumor-1）激活或抑制纤维化基因表达。这些相互作用的途径是由抗纤维化的micro-RNA，miR-31，和促纤维化的氧化剂生成酶，NADPH氧化酶-4（NOX 4）控制。该tPPG将建立概念验证，并提供支持在实验动物模型和IPF患者的细胞/组织中重构miR-31和/或抑制N 0X 4的表达/活化的治疗功效的基本临床前数据，从而迅速导致针对该难治性肺病的I/II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.