Mechanosensor Function in the Control of Gas Exchange Surface Size and Composition

PROJECT SUMMARY/ABSTRACT With each inhalation, exhalation and across development, maturation, aging and pathogenesis, the lung is constantly under mechanical tension. How the biophysical force is sensed and responded to remains poorly understood. In the gas exchange region that bears the front of this force, tension is distributed across the vast alveolar surface. In this study, we will investigate the central premise that mechanical tension, sensed by alveolar epithelial cells, triggers a molecular feedback loop that drives the generation and regeneration of the gas exchange surface area. At the center of this feedback loop is Piezo, a large membrane localized channel that is a quintessential mechanosensor. First discovered and studied in neurons, Piezo genes are also widely expressed in the lung. Our preliminary data show that while loss of Piezo genes in the lung mesenchyme or the endothelium did not lead to discernable alveolar structural defects, inactivating these genes, especially Piezo2, in the lung epithelium led to alveolar simplification in the early postnatal lung. In the adult lung, Piezo2 loss in the alveolar epithelium led to drastically increased susceptibility to alveolar damage, leading to fibrosis. In this study, we will investigate the nature of this mechanosensory circuit in development (Aim 1) and injury repair (Aim 2). The findings will advance our knowledge on how mechanosensation could tune the size and composition of the alveolar surface.