YAP and TAZ regulate alveolar epithelial cell regeneration during lung repair

Pulmonary fibrosis (PF) is a chronic relentlessly progressive interstitial lung disease resulting in progressive loss of respiratory function leading to death of approximately 50,000 patients in the U.S. each year. Failure of normal epithelial repair processes is believed to play a central role in the development and progression of pulmonary fibrosis, leading to the loss of normal alveolar type 1 (AT1) and alveolar type 2 (AT2) and accumulation of alveolar epithelial cells that abnormally co-express genes associated with both AT1, AT2 and proximal airway epithelial cells. In order to understand how abnormal alveolar repair contributes to PF disease mechanisms, we must first determine the critical cellular and molecular mechanisms that facilitate normal alveolar repair and regeneration. Our prior studies and preliminary data indicate that the Hippo-Yap/Taz signaling pathway is an important regulator of alveolar development and promotes both AT2 proliferation and early AT1 specification during alveolar repair, but persistent and inappropriate activation of Yap/Taz signaling may prevent normal AT2/AT1 differentiation and underlie the dysfunctional epithelial repair seen in PF lungs. During adaptive repair of experimental fibrotic injury Yap is dynamically expressed in AT2 cells peaking at 7 days post-injury, while Taz is highest at 14 days post-injury in AT2 cells and readily expressed in most AT1 cells during homeostasis and repair suggesting distinct cell type- specific roles for Yap and Taz. Others have found that deletion of Taz in AT2 cells prevents AT1 differentiation and deletion of Yap/Taz in AT1 cells leads to a loss of AT1 cell identity. This leads to our over-arching hypothesis that dynamic, cell-type-specific, regulation of Yap and Taz activity is essential to guide adaptive alveolar regeneration. To test this overarching hypothesis will assess the concept that Yap and Taz have distinct and cell-type specific interaction partners that mediate transcriptional and epigenetic activity that guide normal lung repair. These concepts will be tested in 2 aims; 1.) To determine the mechanisms by which Yap regulates AT2 cell proliferation and transitional cell differentiation during alveolar repair, and 2.) To define the role of active Taz signaling in the differentiation, maturation, and maintenance of AT1 cells. To test these Aims we will use combinations of in-vivo genetic mouse models, in-vitro organoid models, and ex-vivo precision-cut- lung-slices to define the role of Yap and Taz during normal and pathologic repair. Successful completion of these aims will provide vital therapeutic strategies to guide adaptive repair and promote the delay or resolution of pulmonary fibrosis. Project Number: 1R01HL176912-01 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: Jason Gokey | Institution: VANDERBILT UNIVERSITY MEDICAL CENTER, NASHVILLE, TN | Award Amount: $811,370 | Activity Code: R01 | Study Section: Special Emphasis Panel[ZRG1 RCCS-M (03)] View on NIH RePORTER: https://reporter.nih.gov/project-details/1R01HL17691201