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Epithelial progenitor cell dysfunction in fibrotic lung disease

纤维化肺疾病中的上皮祖细胞功能障碍

基本信息

批准号：
10450042
负责人：
Barry R Stripp
金额：
$ 43.26万
依托单位：
CEDARS-SINAI MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10450042
关键词：
Address Allografting Alveolar Alveolus Basal Cell Basal Cell Hyperplasia Behavior Bleomycin Cells Cessation of life Chronic Chronic lung disease Consensus Data Defect Development Distal Epithelial Exposure to Fibrosis Functional disorder Funding Gene Expression Profile Genomic approach Goals Graft Rejection Human Hyperplasia Idiopathic Interstitial Pneumonia Immune Immunization Impairment Injury Knowledge Lead Link Lung Lung Capacity Lung Transplantation Lung diseases Maintenance Mediating Mesenchymal Modeling Molecular Mus Natural regeneration Normal tissue morphology Pathologic Pathway interactions Patients Play Process Production Pulmonary Fibrosis Pulmonary alveolar structure Regenerative capacity Regulation Role Secretory Cell Signal Transduction Site Specialized Epithelial Cell Structure Structure of parenchyma of lung TP53 gene Testing Therapeutic Tissues Up-Regulation Usual Interstitial Pneumonia Work airway epithelium airway repair alveolar epithelium base cell type cytokine epithelial stem cell expectation fibrotic lung disease idiopathic pulmonary fibrosis immune activation influenza infection injured insight interleukin-22 interleukin-23 lung allograft lung regeneration mouse model novel novel therapeutics pulmonary function pulmonary function decline recruit repaired restoration stem cell function stem cells three dimensional cell culture tissue repair

项目摘要

ABSTRACT Fibrotic lung diseases including usual interstitial pneumonia/idiopathic pulmonary fibrosis (IPF) and chronic lung allograft dysfunction (CLAD) are associated with defects in epithelial maintenance and repair that lead to irreversible declines in lung function and death. However, little is known of mechanisms leading to defective epithelial maintenance and remodeling in lung tissue of these patients. Over the previous funding period we demonstrated that loss of alveolar type 2 (AT2) cells in lung tissue of patients with end-stage IPF is associated with distal airway basal and secretory cell hyperplasia. Using state-of-the-art 3D culture models and genomics approaches we found that alveolar epithelial progenitor (AT2) cells from lungs of IPF patients have reduced colony-forming and clonogenic potentials and accompanying upregulation of the p53 pathway. Alveolar progenitor cell dysfunction in mouse models was found to be a potent regulator of small airway basal cell expansion similar to that observed in lungs of IPF patients. Basal cell expansion could be activated by interleukin 22, a cytokine that was induced following alveolar injury and whose elevated abundance has been associated with fibrotic lung disease. Goals of the present application are to determine cellular mechanisms that contribute to either regeneration or remodeling and molecular pathways that guide cells along either of these pathways with the long-term expectation that novel therapies can be developed to promote normal tissue repair and/or block fibrosis. Our experimental plan will address the overarching hypothesis that p53-dependent alveolar progenitor cell dysfunction drives airway and parenchymal remodeling through a mechanism involving IL23-mediated innate immune stimulation and elevated IL22 production. This hypothesis will be tested in two aims that will define roles for p53 signaling in regulation of alveolar progenitor cells and define roles for IL22 in the regulation of basal cell expansion and recruitment to regions of alveolar injury. Completion of aims will yield novel insights into the molecular regulation of airway epithelial progenitor cells that will guide development of new therapies to treat patients with chronic lung disease.

摘要