Role for Wnt/beta-catenin signaling in alveolar repair and fibrosis

描述（由申请人提供）：肺纤维化是一种毁灭性疾病，其死亡率超过许多恶性肿瘤。纤维化主要由炎症驱动的模型尚未被证明转化为皮质类固醇的有效治疗。因此，需要对肺纤维化机制有新的分子认识。Wnt/(-catenin)信号是维持成人组织稳态的细胞分化决策所需的主要途径，最近被认为与纤维化有关。由于组织纤维化被认为需要上皮细胞破坏和成纤维细胞激活，我们假设Wnt/(-catenin)信号通过靶向肺上皮细胞和成纤维细胞的增殖、存活和分化来驱动成纤维表型。在本提案中，我们将利用表现出减弱（LRP5-/-）或增强（AXIN2-/-） (-catenin信号传导（Aim 1）的小鼠模型，建立Wnt/(-catenin信号传导在博来霉素肺纤维化模型中的因果作用。在博来霉素模型的损伤阶段，我们将确定Wnt/(-catenin)信号的激活是否需要肺泡2型（AT2）上皮细胞的存活及其肺损伤后的修复能力（Aim 2）。在博来霉素模型的成纤维期，我们将确定在成纤维细胞中观察到的Wnt/(-catenin)信号的激活是否促进了它们的增殖和迁移活动。(3)为目标。我们假设有限的Wnt/(-catenin)信号激活促进了肺泡上皮细胞的存活和分化，揭示了在损伤后肺泡修复的早期阶段的重要保护作用。然而，纤维母细胞中Wnt/(-catenin)信号的持续激活最终通过促进其增殖和迁移来驱动成纤维表型。本研究旨在证明Wnt/(-catenin)信号传导与肺纤维化之间的第一个因果关系。通过分析Wnt/(-catenin)信号在肺泡上皮和成纤维细胞成分中的作用，我们将为纤维化肺疾病的诱发原因提供急需的见解。

DESCRIPTION (provided by applicant): Pulmonary fibrosis is a devastating disease with mortality rates that exceed those of many malignancies. Models that fibrosis is largely driven by inflammation have not proven to translate into effective therapy with corticosteroids. Thus, new molecular insights into the mechanism of pulmonary fibrosis are needed. Wnt/(-catenin signaling is a major pathway required for cell differentiation decisions that maintain adult tissue homeostasis, and has recently been implicated in fibrosis. Since tissue fibrosis is thought to require both epithelial destruction and fibroblast activation, we hypothesize that Wnt/(-catenin signaling drives the fibrogenic phenotype by targeting proliferation, survival and differentiation in both lung epithelial cells and fibroblasts. In this proposal, we will establish a causal role for Wnt/(-catenin signaling in the bleomycin model for lung fibrosis, using mouse models that manifest attenuated (LRP5-/-) or enhanced (AXIN2-/-) (-catenin signaling (Aim 1). During the injury phase of the bleomycin model, we will determine whether activation of Wnt/(-catenin signaling is required for the survival of alveolar type 2 (AT2) epithelial cells and their ability to repair after lung injury (Aim 2). During the fibrogenic phase of the bleomycin model, we will determine whether the activation of Wnt/(-catenin signaling observed in fibroblasts promotes their proliferation and migratory activities. (Aim 3). We hypothesize that limited Wnt/(-catenin signaling activation promotes alveolar epithelial cell survival and differentiation, revealing an important protective role during the early stages of alveolar repair after injury. Sustained activation of Wnt/(-catenin signaling in fibroblasts, however, ultimately drives the fibrogenic phenotype by promoting their proliferation and migration. The findings of this proposal aim to demonstrate the first causal link between Wnt/(-catenin signaling and pulmonary fibrosis. By parsing the effects of Wnt/(-catenin signaling in both alveolar epithelial and fibroblast components, we will provide much needed insight into the instigating causes of fibrotic lung diseases. PUBLIC HEALTH RELEVANCE: Pulmonary fibrosis encompasses a broad class of diseases, which affect 5 million people world-wide and approximately two-hundred thousand people in the United States. From the onset of symptoms, the median survival time is only 28 months. There are currently no effective therapies for pulmonary fibrosis, and recent clinical trials have produced disappointing results. Thus, new insights into the mechanisms of pulmonary fibrosis are needed to generate novel therapeutic treatments.