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Mechanistic Targets in Acute Lung Injury

Our lab is interested in the mechanisms of lung vascular endothelial cell dysfunction in acute lung injury (ALI). ALI is a common cause of respiratory failure in critically ill patients, and has a high mortality rate of 25-30%. This is primarily due to a lack of curative interventions. Our mission is to understand the processes underlying the development and resolution of ALI, with the ultimate goal of identifying therapeutic targets to resolve the injury in patients.

We use a creative integration of in vitro and in vivo studies to identify the pathways of endothelial cell inflammation and permeability, and assess the relevance of these pathways in the setting of ALI in mice. The premise is that pulmonary endothelial cells not only serve to separate the blood contents from the extravascular space, but also provide the first barrier for inflammatory cells migrating to the interstitial and alveolar space; hence, they offer an attractive cellular context for targeting the detrimental and/or promoting the beneficial signaling events to limit or reverse ALI.

Current projects in the lab are investigating the role of spleen tyrosine kinase (Syk), mechanistic target of rapamycin (mTOR), and autophagy in regulating endothelial cell responses in ALI.  Our novel and exciting findings that Syk and autophagy promote whereas mTOR limits endothelial inflammation form the basis of our ongoing research to identify the mechanistic basis of their actions, and evaluate the protective and therapeutic benefit of modulating them, either alone or in combination, against ALI.

In a nutshell, research in our lab uses genetically modified mice, primary endothelial cells, and multidisciplinary approaches ranging from biochemical, cellular, and molecular biology to in vivo gene delivery (cell-specific transfer of genes and shRNA to lung endothelium) and multiple mouse models of ALI to identify viable therapeutic targets and mechanisms to limit or reverse ALI.