GasderminD regulation of Acute Lung Injury

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Abstract: The loss of lung endothelial barrier function and endothelial cell (EC) death is a primary pathogenic feature of acute respiratory distress syndrome (ARDS). Although it appears that fundamental immune cell processes are at the core of ARDS-mediated vascular injury and dysfunction, the actual mechanism of endothelial cell death regulated by immune cells remains largely unknown. As a result there are currently no effective pharmacologic therapies. In order to develop more effective therapeutic strategies, it is therefore necessary to understand the precise mechanisms that link immune cell function to vascular dysfunction. This proposal focuses on a new molecular paradigm whereby immune cells (monocytes) drive endothelial cell death. Our extensive supportive data have lead us to formulate the overarching hypothesis that links lung endothelial injury during ARDS to the pyroptotic function of monocyte/macrophage derived GasderminD (GsdmD) encapsulated in circulating microparticles(MP) in association with purinergic receptor, P2X7. To determine the specifics of this novel pathway, we propose the following specific aims. In Aim1, we will delineate the role of monocyte derived GasderminD in mediating endothelial pyroptosis in the mechanism of ALI. We will use available murine model along with in vitro and ex vivo model of ARDS patients to study GsdmD mediated endothelial injury. In Aim2, we will determine the regulation of MP encapsulated GsdmD’s cytopathic function by monocytes. We will study the mechanism how phosphorylation of GasderminD regulates its cytopathic behavior and vulnerability to ubiquitin-mediated degradation. Finally, in Aim3, we will delineate the role of P2X7 in the mechanism of MP GsdmD mediated endothelial cell death. We will study the mechanisms of extracellular MP-associated GsdmD engagement to target cells mediated by the functional purinergic receptor P2X7. These studies will be the first to elucidate the injurious behavior of extracellular GsdmD in coordination with the purinergic receptor, P2X7 encapsulated in MPs, which may play a central role in lung injury. Execution of these studies will lay the foundation for a significant mechanistic advance regarding the cellular interplay between immune cells and endothelia that may provide opportunities for devising novel therapeutic targets that lessen the severity of lung vascular injury.