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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：
8204400
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
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/8204400
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.

项目概述：肺纤维化是一种毁灭性的疾病，其死亡率超过很多恶性肿瘤的症状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，新的分子见解的机制，肺纤维化是必要的。Wnt/β-catenin信号通路是细胞增殖和分化所需的主要途径。维持成体组织稳态的分化决定，最近被牵连在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增殖驱动纤维发生表型，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，在肺纤维化博来霉素模型中Wnt/b-连环蛋白信号传导的因果作用表现出减弱的（LRP 5-/-）或增强的（AXIN 2-/-）b-连环蛋白信号传导（Aim 1）。在受伤期间在博来霉素模型的第一阶段，我们将确定Wnt/β-连环蛋白信号传导的激活是否是博来霉素模型的第二阶段。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所需 (Aim 2）。在博莱霉素模型的纤维化阶段，我们将确定活化是否在成纤维细胞中观察到的Wnt/β-连环蛋白信号转导促进其增殖和迁移活性。 (Aim 3）。我们假设有限的Wnt/β-连环蛋白信号激活促进肺泡上皮细胞存活和分化，揭示了肺泡早期阶段的重要保护作用损伤后修复。然而，在成纤维细胞中Wnt/b-连环蛋白信号的持续激活，通过促进它们的增殖和迁移来驱动纤维化表型。这项研究的结果该提案旨在证明Wnt/b-连环蛋白信号传导与肺动脉高压之间的第一个因果关系。纤维化通过分析Wnt/b-catenin信号在肺泡上皮细胞和成纤维细胞中的作用，通过这些组成部分，我们将提供对纤维化肺病诱发原因的急需见解。