Tracheal occlusion and nuclear YAP activation in the congenital diaphragmatic hernia fetal lung

About This Grant

PROJECT SUMMARY/ABSTRACT Congenital diaphragmatic hernia (CDH) is polygenic condition in which the fetal intestines and liver herniate into the thoracic cavity, resulting in lung compression and impaired pulmonary development. Despite being one of the most common and expensive surgical birth defects managed in neonatal intensive care units worldwide, the underlying biomolecular mechanisms of CDH lung hypoplasia remain unknown. Advances in state-of-the-art surgical critical care, including novel pharmacologic agents and extracorporeal membrane oxygenation, have failed to make a substantial impact in improving clinical outcomes in severely affected children, with an overall mortality remaining at 30%, largely due to the devastating degree of lung pathology. There remains a critical need to better understand CDH lung development to offer hope for affected patients. Our overall objective is to examine the mechanistic impact of an experimental prenatal surgical therapy, known as fetoscopic tracheal occlusion (FETO), and YAP/TAZ on CDH lung development. The mechanism of FETO’s impact on reversing CDH lung hypoplasia remains unknown. YAP/TAZ is the core kinase of the Hippo signaling pathway that has been shown to respond to mechanosensory stimuli during fetal lung patterning and differentiation. The proximal-distal fetal lung abnormalities observed with the human CDH phenotype are consistent with those of YAP/TAZ dysregulation in the setting of mechanical compression (reduced intrapulmonary pressures). Although transpulmonary pressures have also been shown to regulate epithelial differentiation, the interplay between FETO and YAP/TAZ translocation are not well understood. Our group has expertise in the creation and manipulation of an experimental CDH mouse model, as well as in the generation of human 3D lung organoids derived from induced pluripotent stem cells in fetuses with CDH. We will leverage these models to address the following aims: (1) To evaluate the role of YAP/TAZ signaling and tracheal occlusion during CDH fetal lung development; and (2) To determine whether tracheal occlusion modulates mechanical compression forces in CDH fetal lung morphogenesis through the YAP/TAZ signaling pathway. These aims are highly feasible given our promising preliminary data and tools currently at our disposal. We hypothesize that YAP/TAZ dysregulation plays an important role in CDH disease pathogenesis and can be reversed by tracheal occlusion. If the proposed aims are achieved, we will have a better understanding of the role of a mechanosensing pathway in CDH lung development and the underpinnings of an experimental prenatal intervention, fetoscopic endotracheal occlusion, and potentially uncover new therapeutic targets for affected children at the more severe end of the disease spectrum.