Friday, May 9, 2025
5/9/2025
MYRF as an Entry Point to Study Mesothelium Function in Lung Development and Injury Repair - PROJECT SUMMARY/ABSTRACT The mesothelium is an overlooked cell type that is also ubiquitous: it is the most external cell layer that encapsulates all internal organs and lines the body cavities. The best-known canonical function of the mesothelium is to produce lubricant to facilitate organ sliding past each other and the body wall. The mesothelium is composed of a single layer of large and flat squamous epithelial cells that is derived from the mesoderm lineage. In the lung, aside from being the site of asbestos-induced mesothelioma, the role of this fundamental cell layer in lung development and injury repair is poorly understood, and is the focus of this study. Our entry point to studying the mesothelium is Myelin Regulatory Factor (MYRF), a transcription factor. Variants in the MYRF gene have been identified in congenital diaphragmatic hernia (CDH) patients. CDH carries a high mortality rate at birth largely due to respiratory distress. In the lung, MYRF is expressed in the mesothelial cells and alveolar type I cells, two large and flat cell types of the mesenchyme and epithelium, respectively. In mice, while inactivation of Myrf in the lung epithelium led to no discernable phenotypes, inactivation of Myrf in the mesenchyme led to a clear CDH phenotype, including organ herniation, lung hypoplasia and lethality at birth. Later inactivation of Myrf bypassed embryonic lethality, revealing a striking subpleural fibrosis phenotype in the postnatal lung. In the adult, bleomycin treatment of these mutant lungs led to exaggerated injury compared to control, implicating subpleural myofibroblasts as a possible contributor to fibrosis progression. In this study, we will use MYRF as an entry point to investigate mesothelium function as a signaling center in lung growth (Aim 1), as an active barrier in homeostasis (Aim 2), and as an instigator of pathogenesis in lung repair (Aim 3). Our findings will delineate the fundamental role of the mesothelium and its quintessential transcription driver MYRF in lung development, homeostasis, injury and repair.
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