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DUOX1 in fibroblast-macrophage cross-talk in pulmonary fibrosis

肺纤维化中成纤维细胞-巨噬细胞串扰中的 DUOX1

基本信息

批准号：
10544804
负责人：
ALBERT VAN DER VLIET
金额：
$ 19.5万
依托单位：
UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2024-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10544804
关键词：
Address Affect Aging Alveolar Alveolar Macrophages Binding Biology Bleomycin Cells Cicatrix Clinical Cysteine Data Derivation procedure Development Disease Elderly Environment Enzymes Epithelial Cells Equilibrium Fibroblasts Fibrosis Flow Cytometry Gene Expression Goals Grant Growth Factor Growth Factor Receptors Heterogeneity Homologous Gene Host Defense Human IGF2 gene IGF2R gene Impairment In Vitro Injury Insulin Leukocyte L1 Antigen Complex Link Lung Lung diseases Macrophage Mediating Mediator Modeling Mucous Membrane Mus Myofibroblast NADPH Oxidase Oxidants Oxidation-Reduction Oxidative Stress Pathogenesis Pathology Patients Persons Population Post-Translational Protein Processing Production Property Proteins Pulmonary Fibrosis Role S100A8 gene Source Structure of parenchyma of lung Suspensions Techniques Technology Tissues Work airway epithelium alveolar epithelium cell type endoplasmic reticulum stress epithelial injury fibrogenesis fibrotic lung human tissue idiopathic pulmonary fibrosis insight mitochondrial dysfunction mortality novel overexpression oxidation

项目摘要

PROJECT SUMMARY Idiopathic pulmonary fibrosis (IPF) is a progressive, deadly disease characterized by the accumulation of scar tissue in the lung. Oxidative stress has frequently been implicated in IPF, but the underlying mechanisms through which altered redox balance contribute to IPF pathogenesis are not fully understood. Recent observations by us and others indicated that the NADPH oxidase homolog DUOX1, normally primarily present in the respiratory epithelium with a main function in mucosal host defense, is increased in lung tissues of humans with IPF and mice with bleomycin-induced pulmonary fibrosis, and largely within non-epithelial cells likely including pulmonary fibroblasts and macrophages. Preliminary findings indicate that DUOX1 also contributes to experimentally- induced fibrosis, especially in aging mice. However, it is still unclear which lung cells are involved in increased DUOX1 expression and its profibrotic functions. In this exploratory grant, we will aim to identify the cellular source of DUOX1 expression during fibrosis, and use cell-specific deletion of DUOX1 to address e.g. fibroblast- or macrophage-specific roles of DUOX1 in pulmonary fibrosis (Specific Aim 1). In an effort to understand the mechanisms by which DUOX1 may promote fibrosis, we identified several DUOX1-interacting proteins, including IGF2R and S100A8/A9, which have been previously linked to fibroblast activation and/or myofibroblast differentiation. Based on this, we will assess interactions of DUOX1 with these and other proteins in normal or fibrotic human and mouse lung tissues, and in fibroblasts or macrophages isolated from these tissues. We will also explore the hypothesis that DUOX1 regulates these proteins functionally by oxidative mechanisms, in isolated fibroblasts or macrophages, by either overexpressing or deleting DUOX1 (Specific Aim 2). Successful accomplishment of these aims will yield novel functional aspects of DUOX1 in macrophage or fibroblast biology, and their contributions to IPF pathology.

项目总结