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

Wnt/β-连环蛋白信号在肺泡修复和纤维化中的作用

• 批准号: 8039510
• 负责人: Cara J Gottardi
• 金额: $ 38.13万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-12-01 至 2014-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8039510
• 关键词: AXIN2 gene; Adrenal Cortex Hormones; Adult; Adult Respiratory Distress Syndrome; Affect; Alveolar; Apoptotic; Attenuated; Biopsy Specimen; Bleomycin; Cell Differentiation process; Cell Proliferation; Cell Survival; Cells; Cessation of life; Clinical Trials; Connective Tissue Diseases; Cyclin D1; Data; Disease; Disease Progression; Dissection; Epithelial; Epithelial Cells; Epithelium; Exhibits; Felis catus; Fibroblasts; Fibrosis; Hamman-Rich syndrome; Homeostasis; Inflammation; Injury; Knockout Mice; Link; Lung; Lung diseases; Malignant Neoplasms; Matrilysin; Microarray Analysis; Modeling; Molecular; Mus; Nuclear; Outcome; Pathway interactions; Patients; Phase; Phenotype; Process; Proteins; Pulmonary Fibrosis; Recovery; Relative (related person); Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Staging; Staining method; Stains; Symptoms; Systemic Scleroderma; Time; Tissue Sample; Tissues; Translating; United States; Up-Regulation; Wound Healing; alveolar epithelium; beta catenin; effective therapy; fibrogenesis; human SFRP4 protein; indium-bleomycin; inhibitor/antagonist; insight; lung development; lung injury; migration; mortality; mouse model; novel; novel therapeutics; protective effect; recombinase; repaired; small molecule; survivin; translational approach

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.

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，需要对肺纤维化的机制进行新的分子见解。Wnt/β-catenin信号传导是维持成体组织稳态的细胞分化决定所需的主要途径，并且最近已经涉及纤维化。由于组织纤维化被认为需要上皮破坏和成纤维细胞活化，我们假设Wnt/β-连环蛋白信号通过靶向肺上皮细胞和成纤维细胞的增殖、存活和分化来驱动纤维化表型。在本提案中，我们将使用表现出减弱的（LRP 5-/-）或增强的（AXIN 2-/-）β-连环蛋白信号传导（Aim 1）的小鼠模型，在肺纤维化的博来霉素模型中建立Wnt/β-连环蛋白信号传导的因果作用。在博来霉素模型的损伤阶段，我们将确定肺泡2型（AT 2）上皮细胞的存活及其在肺损伤后的修复能力是否需要Wnt/β-连环蛋白信号传导的激活（Aim 2）。在博来霉素模型的纤维化阶段，我们将确定在成纤维细胞中观察到的Wnt/β-连环蛋白信号传导的活化是否促进其增殖和迁移活性。(Aim 3）。我们假设有限的Wnt/β-catenin信号激活促进肺泡上皮细胞的存活和分化，揭示了损伤后肺泡修复早期阶段的重要保护作用。然而，成纤维细胞中Wnt/β-连环蛋白信号的持续激活最终通过促进其增殖和迁移来驱动纤维化表型。本研究的目的是证明Wnt/β-catenin信号与肺纤维化之间的第一个因果关系。通过分析Wnt/β-catenin信号在肺泡上皮细胞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。 公共卫生关系：肺纤维化包括广泛的一类疾病，其影响全世界500万人和美国约20万人。从出现症状算起，中位生存时间只有28个月。目前没有有效的治疗肺纤维化的方法，最近的临床试验产生了令人失望的结果。因此，需要对肺纤维化机制的新见解来产生新的治疗方法。