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 the diseases that are commonly in American Veterans. The future research focuses on the role of focal adhesion kinase (FAK) in the regulation of gut barrier injury during trauma. Additional efforts will be devoted in collaboration with VA surgeons to examining molecular mechanisms of endothelial barrier dysfunction and MMP dysregulation that lead to the failure of vascular remodeling in VA patients. 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. The intestinal epithelial barrier damage in burns, a major form of trauma, has not been well characterized clinically. In addition, its cellular and molecular mechanisms remain incompletely understood. The major goal of application is to elucidate the cell-specific mechanisms of leaky guts during thermal injury. We hypothesize that thermal injury induced inflammation in gut tissue activates Src and FAK activity in intestinal epithelium, stimulate focal remodeling and ZO1 mediated junction disassociation therefore impairing gut epithelial barrier integrity. The specific goals developed in this study are: 1) to analyze the molecular mechanism of FAK mediated gut epithelial barrier dysfunction, and 2) to evaluate the functional role of FAK activation and therapeutic potential of FAK inhibition in gut barrier dysfunction during thermal 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 to establish a new molecular pathway in the regulation of tight and adherens junctions. Information gleaned from the research work will not only contribute to the advancement of gastrointestinal pathobiology, but also has clinical implications in the development of effective therapies or surgical interventions against gut barrier injury in the VA patients with trauma and inflammatory bowel diseases.
Trauma is a major cause of mortality and morbidity in American soldiers and veterans. As a typical form of trauma, thermal injury results from flame/chemical burns in combat or anti-terrorist actions. Despite the improved critical care and wound management, posttraumatic complications remain a life-threatening problem that causes extended hospital stay and charges. The gut plays an important role in the development of multiple organ complications following a severe burn. Gut barrier failure contributes to systemic inflammatory syndrome and sepsis by serving as the major site of blood leakage and bacteria translocation. The mechanisms of leaky guts are poorly understood. This study provides a comprehensive evaluation of the molecular pathways leading to gut hyperpermeability during burn. This research work has the potential to impact the development of surgical or medical interventions against gut barrier injury in VA patients with trauma or inflammatory bowel disease.
