Role of miRNA-27a Regulation of VAV3 in Cellular and Experimental Models of Sepsis-induced Acute Respiratory Distress Syndrome

We identified miR-27a as a differentially regulated miRNA ARDS, and its putative targets play roles in lung injury. Our studies focus on the target VAV3, a GEF for Rho GTPases. VAV3 signalling cascades play roles in cytoskeletal organization of endothelial cells, which is shown to be involved in cell adhesion, migration, and maintaining barrier integrity. We hypothesize that miR-27a is overexpressed in models of ARDS while VAV3 is suppressed; regulating VAV3 via miR-27a would impact inflammatory phenotypes such as barrier integrity; and inhibiting miR-27a would attenuate inflammatory phenotypes. We aim to verify the regulation of VAV3 by miR-27a, show phenotype changes in vitro through miR-27a modulation, and replicate the findings in vivo. We find that inflammatory stimuli stimulate miR-27a expression to suppress VAV3. Loss of VAV3 disrupts endothelial barrier integrity, leading to increased adhesion and transendothelial migration of leukocytes, thus promoting inflammation. Inhibiting miR-27a would partially attenuate the inflammatory response.M.Sc