Research Project: Pulmonary Endothelial NEDD9 and Acute Lung Injury
Funded by the American Lung Association’s Accelerator Program and the Harold Amos Medical Faculty Development Program
Acute respiratory distress syndrome (ARDS) is associated with ~30-40% in-hospital mortality and long-term morbidity among survivors. There is a critical need to identify novel therapeutic targets to improve short- and long-term outcomes in ARDS patients. The pathobiology of ARDS is heterogenous, but one common feature is acute pulmonary endothelial injury with immune activation, platelet aggregation and microthrombosis. We have demonstrated NEDD9 is a pulmonary endothelial protein that (1) binds activated platelets to promote platelet-endothelial adhesion in vitro and in vivo, and (2) can be targeted by a custom-made anti-NEDD9 antibody (Ab-N9) to prevent pulmonary vascular thrombosis in vivo. Here, we present preliminary data demonstrating that in ARDS patients, pulmonary endothelial NEDD9 expression is increased and co-localizes with intraluminal thrombus in situ. Thus, we hypothesize that NEDD9 inhibition will attenuate the extent of lung injury by decreasing platelet-endothelial adhesion and consequent inflammatory cell recruitment. To investigate this, we will use existing NEDD9-/- mice and our anti-NEDD9 antibody to interrogate the endothelial consequences of NEDD9 inhibition during sterile lung injury (Aim 1), pulmonary host-pathogen interactions (Aim 2), and post-injury endothelial repair (Aim 3). This will position the applicant to be an independent translational investigator of acute lung injury and advance NEDD9 antagonism as a potential therapeutic target in ARDS.