Friday, April 26, 2024
4/26/2024
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.
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