Focal adhesion kinase regulation of lung vascular permeability and edemagenesis

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DESCRIPTION (provided by applicant): Loss of lung vascular barrier function and inflammatory cell infiltration are two cardinal features of acute lung injury (ALI). The project wil investigate the fundamental concept that endothelial focal adhesion kinase (FAK) modulates the increase in lung vascular permeability and the inflammatory response by suppressing intracellular Ca2+ rise. We will test the hypothesis that FAK induces microRNA-150 (miR-150) expression which targets the Ca2+ sensor, stromal interacting molecule 1 (STIM1). We postulate that STIM1 downregulation by this mechanism is crucial for blocking Ca2+ signaling in endothelial cells and thereby prevents disruption of lung vascular barrier and inflammation. To address this hypothesis, we have generated a novel tamoxifen-inducible endothelial cell (EC)-specific FAK knockout (EC-FAK-/-) as well as EC-STIM1-/- mouse models. We will address the following aims: Aim #1, To define the role of FAK in regulating lung fluid balance and modulating lung inflammation using endothelial cell-specific FAK null mice; Aim #2, To determine the role of FAK in suppressing STIM1 activity and thereby blocking Ca2+ entry signals mediating increased lung vascular permeability and inflammation; and Aim #3, To define the role of miR-150 as an essential effector of FAK that targets STIM1 and thus prevents increased lung vascular permeability and inflammation. These studies will use a combination of imaging, genetic, and physiological approaches to develop a comprehensive and integrated picture of the role of endothelial FAK in regulating lung fluid homeostasis and inflammation. The results of these studies will have the potential of defining novel therapeutic targets directed against ALI. PUBLIC HEALTH RELEVANCE: Acute lung injury (ALI) characterized by plasma leakage, increased white blood cell influx and cytokine generation is a life threatening disease. Although great strides have been made in effectively supporting ALI patients, current treatment strategies have demonstrated limited success in preventing ALI. Therefore the search continues for more effective treatments to reduce the unacceptably high rate of mortality caused by ALI. Proposed studies will investigate the role of endothelial protein, focal adhesion kinase (FAK) in maintaining lung fluid homeostasis and moderating lung inflammatory injury. We hope these studies will offer novel insights and therapeutic targets that we think will lead to the developmen of more effective treatments with improved outcomes for patients suffering from ALI.