Mechanobiology of Lung Fibrosis

描述(申请人提供)：纤维化是许多组织和疾病共同的病理生物学过程，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。目前还没有成功阻止或逆转纤维化的治疗方法，这是一个重要的未得到满足的临床需求。纤维化主要发生在软组织(肺、肝、肾、心脏、皮肤)，通过成纤维细胞过度激活而达到收缩/增殖/凋亡抵抗状态，并伴随细胞外基质的沉积。我们已经发现，成纤维细胞对基质硬度的变化非常敏感；这一发现对正常和疾病来源的成纤维细胞都是正确的，并跨越了正常和纤维化肺组织的硬度范围。在这个项目中，我们试图剖析一条新的将基质僵硬与成纤维细胞激活联系起来的分子通路，并测试这一通路是否与人类纤维化有关，以及在 推动模型系统中的纤维化。我们专注于转录共激活因子YAP和TAZ，它们在进化上是器官大小、细胞周期和干细胞功能的保守调节因子。我们的初步数据显示，YAP/TAZ在人IPF组织中的核定位增强，并有力地支持了YAP和TAZ在成纤维细胞激活中的重要作用，这两个调控因子是成纤维细胞生物学的两个关键调节因子。我们假设YAP和TAZ是机械激活的肺纤维化调节剂，协调和整合成纤维细胞基质僵硬和生化反应，导致一系列促纤维化功能的级联，从而推动进行性纤维化。我们将使用与人类疾病相关的体外、小鼠和人类组织模型，从两个方面评估这一假说。拟议的研究将通过阐明一个新的汇合点，将机械和生化信号与成纤维细胞激活和肺纤维化联系起来，从而推动该领域的发展。如果成功，拟议的研究可能会为开发针对肺和其他软组织纤维化的YAP和TAZ的治疗开辟新的途径。

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.