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: 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
• 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

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：肺纤维化是一种死亡率超过这些的毁灭性疾病