BLRD Research Career Scientist Award Application

Project Summary Trauma-induced inflammation and multiple organ failure are major causes of mortality and morbidity in American soldiers and veterans. Gut barrier dysfunction plays a critical role in the development of posttraumatic complications by providing the major site for plasma leakage and bacterial translocation. Leaky gut, a consequence of gut barrier damage during trauma, has not been treated effectively. The pathology of leaky gut has not been fully characterized and its cellular and molecular mechanisms remain incompletely understood. The overall objective of this application is to expand my current project towards a new phase to further investigate the molecular control of cell specific mechanisms that contribute to leaky gut during trauma and subsequent acute lung injury. We hypothesize that thermal injury induced inflammation in gut tissue activates focal adhesion pathways in intestinal epithelium resulting in epithelial junction disassociation, therefore, impairing gut epithelial barrier integrity. The project will focus on 1) to analyze the molecular mechanism of FAK mediated gut epithelial barrier dysfunction; 2) to evaluate the role of FAK activation and therapeutic potential of FAK inhibition; 3) to identify and characterize leaky gut-produced circulator factors that contribute to lung injury. The study design employs complimentary in vivo, ex vivo, and in vitro models that incorporate molecular and genetic approaches into physiological experiments under clinically relevant trauma conditions. The significance of the study lies in its potential not only to contribute to the advancement of gastrointestinal pathobiology, but also to have clinical implications in the development of effective therapies or surgical interventions against gut barrier injury. In addition, the funding will support PI’s effort to participate in the VA services and the collaboration with VA physicians and scientists.