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

• 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
• 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

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.

项目摘要 特发性肺纤维化（IPF）是一种进行性、致死性疾病，其特征在于瘢痕的积累 肺部组织氧化应激经常与IPF有关，但通过氧化应激的潜在机制可能与IPF有关。 氧化还原平衡的改变导致IPF发病机制尚未完全清楚。我们最近的观察 其他研究表明，通常主要存在于呼吸道的NADPH氧化酶同源物DUOX 1， 在粘膜宿主防御中具有主要功能的上皮细胞在患有IPF的人的肺组织中增加， 博来霉素诱导的肺纤维化小鼠，并且很大程度上在非上皮细胞内，可能包括肺 成纤维细胞和巨噬细胞。初步研究结果表明，DUOX 1也有助于实验- 诱导纤维化，特别是在衰老的小鼠中。然而，目前还不清楚哪些肺细胞参与了增加的肺细胞增殖。 DUOX 1的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 的DUOX 1表达，并使用DUOX 1的细胞特异性缺失来解决例如成纤维细胞-或 DUOX 1在肺纤维化中的巨噬细胞特异性作用（特异性目的1）。为了理解 DUOX 1可能促进纤维化的机制，我们鉴定了几种DUOX 1相互作用蛋白，包括 IGF 2 R和S100 A8/A9，先前已与成纤维细胞活化和/或肌成纤维细胞 分化在此基础上，我们将评估DUOX 1与这些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分离的成纤维细胞或巨噬细胞中。我们将 还探讨了DUOX 1通过氧化机制在功能上调节这些蛋白质的假设， 分离的成纤维细胞或巨噬细胞，通过过表达或缺失DUOX 1（特异性目的2）。成功 这些目标的实现将产生DUOX 1在巨噬细胞或成纤维细胞生物学中的新功能方面， 及其对IPF病理学的贡献。