Vascular leakage resulting from endothelial barrier dysfunction is a common mechanism of multiple organ failure that mainly contributes to the morbidity and mortality in patients with sepsis. Identifying novel therapeutic targets that can effectively maintain vascular integrity is crucial to treat septic patients. The intercellular adhesion protein vascular endothelial (VE)-cadherin is the most important molecule in forming the adherens junctions, as well as regulating the endothelial barrier function. VE–cadherin expression in cell-cell junctions is stabilized by binding to p120-catenin (p120). Our preliminary data indicate that p120 sumoylation plays a crucial role in regulating the interaction of p120 and VE-cadherin and endothelial barrier function in sepsis. In this proposal, we will test the hypothesis that p120 sumoylation is the critical determinant of p120- VE-cadherin dissociation, endothelial barrier dysfunction and vascular endothelial hyperpermeability during sepsis. Two Specific Aims are proposed as follows: Aim 1. To elucidate the molecular mechanisms by which p120 sumoylation regulates endothelial barrier function during sepsis. Aim 2: To evaluate the role of p120 sumoylation in vascular leakage and survival during polymicrobial sepsis and test the therapeutic potential of targeting p120 sumoylation for treating septic injury. These comprehensive studies will utilize genetic, imaging, pharmacological and physiological approaches to investigate molecular mechanisms of p120 sumoylation in the regulation of endothelial barrier integrity and assess the therapeutic potential of inhibition of p120 sumoylation in improving lung edema and survival during sepsis.