Regulation of type II cells in the repair ofalveolar epithelial injury

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Title: Regulation of type II cells in the repair of alveolar epithelial injury ABSTRACT Each year in the United States, there are ~ 200,000 cases of acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) . Repair of the injured alveolar epithelial barrier is essential for the resolution of ALI/ARDS. However, there is currently a lack of targeted therapies aimed at promoting the repair of the epithelium to restore barrier function. The goal of this project is to understand the signaling events contributing to the endogenous alveolar repair process and identify potential drug targets to accelerate repair. Lung alveoli are lined with two types of epithelial cells: Alveolar Type I cells (AT1) and Type II cells (AT2). AT1 cover ~95% of the surface area because of their thin and squamous shape and are responsible for blood-gas exchange. AT2 have multiple functions including the secretion of surfactant and are also able to act as progenitor cells, proliferating and converting to AT1 after lung injury to restore the alveolar epithelial barrier. However, the signaling events responsible for regulating AT2-mediated repair remain poorly understood. Our preliminary data demonstrated the requirement of a non-canonical Notch ligand Dlk1 (For delta-like 1 homolog) in the AT2 to AT1 differentiation. We found that a dynamic change in Dlk1 expression is correlated with the AT2 to AT1 transition during repair. Using a mouse model in which Dlk1 was specifically disrupted in AT2, we found that the mutant cells were unable to differentiate into AT1 and at mean time had abnormally elevated Notch signaling. Based on these data, we hypothesize that dynamically regulated Notch signaling is essential for the proper progenitor function of AT2 and that Dlk1 plays an essential role in the AT2 to AT1 transition during alveolar repair by inhibiting Notch signaling. We intend to pursue the following specific aims: Aim 1: To test the hypothesis that Dlk1 regulates the AT2 to AT1 transition required for alveolar repair. We will determine the function of Dlk1 in restoring epithelial barrier integrity and gas-exchange function post-injury. We will define the detailed steps in the Dlk1 regulated AT2 to AT1 transition and identifying factors downstream and upstream of Dlk1. Aim 2: To test the hypothesis that the Dlk1-dependent dynamic regulation of the canonical Notch signaling pathway is essential during AT2-mediated alveolar repair. We will determine the role of Notch signaling activity in AT2 at different phases of alveolar repair and investigate the molecular interactions between Dlk1 and Notch receptors and ligands. Finally, we will investigate the effects of improving alveolar repair through the introduction of Dlk1 and other Notch-regulating molecules into alveoli and will further test the roles of Notch/Dlk1 in human AT2 and human iPSC derived AT2. At the conclusion of these studies, we will have filled an important gap in knowledge about the molecular mechanisms underlying alveolar repair. We believe that these studies will lead to the discovery of therapeutic targets to accelerate lung repair and prevent chronic pathological conditions resulting from improper recovery.