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：
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
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/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

项目摘要

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，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证明可以转化为皮质类固醇的有效治疗。因此，需要对肺纤维化机制的新分子见解。 Wnt/（ - 链氨蛋白信号传导是维持成人组织稳态的细胞分化决策所需的主要途径，最近与纤维化有关。由于认为组织纤维化需要上皮细胞破坏和成纤维细胞激活，我们假设Wnt/wnt dnt/catenin信号通过纤维化的拟合分化的拟合型拟合型，并脱离了纤维化的生存，并差异化的拟合型物均活化的现场构成型物均活化的现象，并构成了生存的替代现象，并构成了均匀的现场构造，并且均可构成量化的现场构成，并构成了生存的量化，并构成了生存的现场构成，并且均可构成型号的生存，并促进了均匀的现场。在此提案中，我们将使用表现出衰减的小鼠模型（LRP5 - / - ）或增强的小鼠模型（AXIN2 - / - ）（-catenin信号（-catenin signal ot ot the Bleymycin of Bleymycin of Bleymycin），bleomycin of bleomycin（a aimction）是否会确定bleymycin（aim bleomycin of Bleomycin of Ble Mymycin），在此提案中，我们将建立Wnt/Wnt蛋白信号的因果作用。肺泡2（AT2）上皮细胞的存活及其在肺损伤后修复的能力（AIM 2）所必需的（我们将确定在成纤维细胞中观察到的Catenin信号的激活是否会促进其增殖和迁移活性。（目标3）。我们假设有限的Wnt/（ - Catenin信号传导激活会促进肺泡上皮细胞的存活和差异化，从而揭示了受伤后肺泡修复的早期阶段的重要保护作用。持续激活Wnt/（ - 在成纤维细胞中的Catenin信号传导，但是，纤维细胞中的Catenin信号最终通过纤维化来促进其迁移的迁移，并促进了这种迁移的迁移，并促进了这种迁移的迁移，并促进了这种迁移的迁移，并促进了迁移的范围。 Wnt/（ - catenin信号传导和肺纤维化之间的因果关系。通过解析Wnt/（ - 链球菌上皮细胞和成纤维细胞成分中的catenin信号传导的影响），我们将非常需要深入了解纤维化肺疾病的启动原因。公共卫生相关性：肺纤维化包括一系列广泛的疾病，在美国，全球500万人和大约200万人影响了500万人。从症状开始时，中位生存时间仅为28个月。目前尚无有效的肺纤维化疗法，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治疗。