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

基本信息

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
项目类别：
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

项目摘要

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，死亡率超过了那些许多恶性肿瘤。纤维化主要由炎症驱动的模型尚未证明转化为有效的皮质类固醇治疗。因此，新的分子见解对需要肺纤维化。 Wnt/B-catenin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策，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，因此我们假设Wnt/b-catenin信号传导通过靶向增殖来驱动纤维型表型肺上皮细胞和成纤维细胞的生存和分化。在此提案中，我们将建立 Wnt/B-catenin信号在博来霉素模型中用于肺纤维化的因果作用，使用小鼠模型这种表现衰减（LRP5 - / - ）或增强（AXIN2 - / - ）B-catenin信号传导（AIM 1）。受伤期间博来霉素模型的阶段，我们将确定Wnt/B-catenin信号的激活是否为肺泡2型（AT2）上皮细胞的存活及其在肺损伤后修复的能力所必需的（目标2）。在博来霉素模型的纤维化阶段，我们将确定是否激活在成纤维细胞中观察到的Wnt/B-catenin信号传导促进其增殖和迁移活性。（目标3）。我们假设有限的Wnt/B-catenin信号传导激活促进肺泡上皮细胞生存和差异化，揭示了肺泡早期的重要保护作用受伤后修复。然而通过促进其增殖和迁移来驱动纤维型表型。这个发现建议旨在证明Wnt/B-catenin信号和肺部的第一个因果关系纤维化。通过解析Wnt/B-catenin信号在肺泡上皮和成纤维细胞中的影响组件，我们将提供急需的洞察力，以了解纤维化肺部疾病的煽动原因。