Mechanobiology of Lung Fibrosis

描述（由申请人提供）：纤维化是许多组织和疾病常见的病理生物学过程，其导致组织重塑和功能丧失，通常需要器官置换或导致终末期疾病。目前没有成功阻止或逆转纤维化的疗法，这代表了显著未满足的临床需求。纤维化主要发生在软组织（肺、肝、肾、心脏、皮肤）中，通过过度的成纤维细胞活化至收缩/增殖/凋亡抗性状态并伴随细胞外基质的沉积。我们发现成纤维细胞对基质硬度的变化非常敏感;这一发现对于正常和疾病来源的成纤维细胞都是正确的，并且跨越了正常和纤维化肺组织中发现的硬度范围。在这个项目中，我们试图剖析一种新的分子途径，将基质硬度与成纤维细胞活化联系起来，并测试这种途径是否与人类纤维化有关，以及在人类纤维化中是否必不可少。 在模型系统中驱动纤维化。我们专注于转录辅激活因子雅普和TAZ，进化上保守的调节器官大小，细胞周期和干细胞功能。我们的初步数据表明，雅普/TAZ在人IPF组织中的核定位增强，并强烈支持雅普和TAZ在基质硬度和TGF-β（成纤维细胞生物学的两种关键调节因子）下游的成纤维细胞活化中的重要作用。我们假设雅普和TAZ是肺纤维化的机械活化调节剂，其协调和整合成纤维细胞基质硬度和生化反应，导致促纤维化功能级联，从而驱动进行性纤维化。我们将使用与人类疾病相关的体外、小鼠和人体组织模型在两个目标中评估这一假设。拟议的研究将通过阐明将机械和生化线索与成纤维细胞活化和肺纤维化联系起来的新的交汇点来推进该领域。如果成功，拟议的研究可能会导致新的途径，为发展靶向雅普和TAZ在肺和其他软组织纤维化的治疗。

DESCRIPTION (provided by applicant): Fibrosis is a pathobiological process common to many tissues and diseases which results in tissue remodeling and loss of function, often necessitating organ replacement or leading to end-stage disease. No therapies are currently available that successfully arrest or reverse fibrosis, and this represents a significant unmet clinical need. Fibrosis occurs predominantly in soft tissues (lung, liver, kidney, heart, skin) through excess fibroblast activation to a contractile/proliferative/apoptosis resistant state and accompanying deposition of extracellular matrix. We have discovered that fibroblasts are exquisitely sensitive to alterations in matrix stiffness; this finding is true for both normal and disease-derived fibroblasts, and spans the stiffness range found in normal and fibrotic lung tissue. In this project, we seek to dissect a novel molecular pathway linking matrix stiffness to fibroblast activation, and test whether this pathway is relevant in human fibrosis and essential in driving fibrosis in model systems. We focus on the transcriptional co-activators YAP and TAZ, evolutionarily conserved regulators of organ size, cell cycle, and stem cell function. Our preliminary data demonstrate enhanced nuclear localization of YAP/TAZ in human IPF tissue, and strongly support an essential role for YAP and TAZ in fibroblast activation downstream of both matrix stiffness and TGF-beta, two pivotal regulators of fibroblast biology. We hypothesize that YAP and TAZ are mechanically activated regulators of lung fibrosis that coordinate and integrate fibroblast matrix stiffness and biochemical responses leading to a cascade of pro-fibrotic functions that drive progressive fibrosis. We will evaluate this hypothesis in two aims using in vitro, mouse and human tissue models relevant to human disease. The proposed studies will advance the field by elucidating a novel point of convergence linking mechanical and biochemical cues to fibroblast activation and pulmonary fibrosis. If successful, the proposed studies could lead to new avenues for development of therapies targeting YAP and TAZ in fibrosis of the lung and other soft tissues.