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: 8386673
• 负责人: Cara J Gottardi
• 金额: $ 36.3万
• 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/8386673
• 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

Project Summary: 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/b-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/b-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/b-catenin signaling in the bleomycin model for lung fibrosis, using mouse models that manifest attenuated (LRP5-/-) or enhanced (AXIN2-/-) b-catenin signaling (Aim 1). During the injury phase of the bleomycin model, we will determine whether activation of Wnt/b-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/b-catenin signaling observed in fibroblasts promotes their proliferation and migratory activities. (Aim 3). We hypothesize that limited Wnt/b-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/b-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/b-catenin signaling and pulmonary fibrosis. By parsing the effects of Wnt/b-catenin signaling in both alveolar epithelial and fibroblast components, we will provide much needed insight into the instigating causes of fibrotic lung diseases.

项目摘要：肺纤维化是一种毁灭性疾病，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，对机制的新分子见解 需要肺纤维化。 Wnt/b-连环蛋白信号传导是细胞所需的主要途径 维持成人组织稳态的分化决定，最近与 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激活， 我们假设 Wnt/b-catenin 信号传导通过靶向增殖来驱动纤维化表型， 肺上皮细胞和成纤维细胞的存活和分化。在本提案中，我们将建立 使用小鼠模型研究 Wnt/b-catenin 信号在博莱霉素肺纤维化模型中的因果作用 表现出减弱的 (LRP5-/-) 或增强的 (AXIN2-/-) b-连环蛋白信号传导（目标 1）。受伤期间 在博来霉素模型的阶段，我们将确定 Wnt/b-catenin 信号传导是否激活 2 型肺泡 (AT2) 上皮细胞的存活及其肺损伤后修复能力所需的 （目标 2）。在博来霉素模型的纤维化阶段，我们将确定激活是否 在成纤维细胞中观察到的 Wnt/b-连环蛋白信号传导促进其增殖和迁移活动。 （目标 3）。我们假设有限的 Wnt/b-catenin 信号激活促进肺泡上皮细胞 存活和分化，揭示了肺泡早期的重要保护作用 受伤后修复。然而，成纤维细胞中 Wnt/b-catenin 信号的持续激活，最终 通过促进纤维化表型的增殖和迁移来驱动纤维化表型。本次调查结果 该提案旨在证明 Wnt/b-catenin 信号传导与肺部疾病之间的第一个因果关系 纤维化。通过解析 Wnt/b-catenin 信号传导对肺泡上皮和成纤维细胞的影响 成分，我们将为纤维化肺病的诱发原因提供急需的见解。