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.

项目概要特发性肺纤维化（IPF）是一种进行性、致命的疾病，其特征是疤痕积累肺部组织。氧化应激经常与 IPF 有关，但其潜在机制是通过氧化还原平衡的改变导致 IPF 发病机制尚不完全清楚。我们最近的观察等人指出 NADPH 氧化酶同源物 DUOX1，通常主要存在于呼吸道中具有粘膜宿主防御主要功能的上皮细胞在 IPF 患者的肺组织中增加，患有博来霉素诱导的肺纤维化的小鼠，并且主要发生在非上皮细胞内，可能包括肺纤维化成纤维细胞和巨噬细胞。初步研究结果表明，DUOX1 也有助于实验- 诱导纤维化，尤其是在衰老小鼠中。然而，目前尚不清楚哪些肺细胞参与了增加 DUOX1 表达及其促纤维化功能。在这项探索性资助中，我们的目标是确定细胞来源纤维化期间 DUOX1 表达的变化，并使用 DUOX1 的细胞特异性删除来解决例如成纤维细胞或 DUOX1 在肺纤维化中的巨噬细胞特异性作用（具体目标 1）。为了努力了解为了了解 DUOX1 促进纤维化的机制，我们鉴定了几种 DUOX1 相互作用蛋白，包括 IGF2R 和 S100A8/A9，先前已被认为与成纤维细胞活化和/或肌成纤维细胞有关差异化。在此基础上，我们将评估正常或正常情况下 DUOX1 与这些蛋白质和其他蛋白质的相互作用。纤维化的人和小鼠肺组织，以及从这些组织中分离的成纤维细胞或巨噬细胞。我们将还探讨了 DUOX1 通过氧化机制功能性调节这些蛋白质的假设，通过过表达或删除 DUOX1 分离成纤维细胞或巨噬细胞（具体目标 2）。成功的这些目标的实现将产生 DUOX1 在巨噬细胞或成纤维细胞生物学中的新功能，以及他们对 IPF 病理学的贡献。