Systemic inflammation and multiple organ failure associated with trauma are a major cause of mortality and morbidity in American soldiers and veterans. Intestinal barrier dysfunction plays an important role in the development of posttraumatic complications such as sepsis by providing the major site for diffusion of toxins, allergens and bacterial translocation to the circulation. Despite the well- recognized importance of gut dysfunction in the pathogenesis of posttraumatic complications, the intestinal permeability response to severe burns, a major form of trauma, has not been well characterized, and its cellular and molecular mechanisms have not been fully understood. The goal of this study is to elucidate the cell-specific mechanisms of leaky guts during thermal injury. The hypothesis to be tested is that thermal injury induced inflammation in gut tissue activates focal adhesion kinase (FAK) activity in gut epithelium, stimulates focal remodeling and epithelial junction disassociation, therefore impairing gut epithelial barrier integrity.
Two specific aims are developed in this proposal to: 1) characterize functional role of FAK mediated intestinal barrier dysfunction and therapeutic potential of FAK inhibition during thermal injury, and 2) explore the molecular mechanism of FAK mediated gut epithelial barrier dysfunction. 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 mechanism in the regulation of gut epithelial barrier function. The data derived from this project will enhance our understanding of pathophysiological mechanisms involved in gut epithelial barrier function. More importantly, it will expand our knowledge of gastrointestinal pathobiology and contribute to the development of effective therapies and surgical interventions against gut barrier injury in patients suffered from trauma or inflammatory diseases.

Public Health Relevance

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 related fire or scald accidents. Despite the improved critical care and wound management, posttraumatic complications remain a life-threatening problem that causes extended hospital stay. The gut plays an important role in developing multiple organ complications following a severe burn. In particular, gut barrier failure contributes to systemic inflammatory syndrome and sepsis. This study provides a comprehensive evaluation of focal adhesion kinase in mediation of intestinal hyperpermeability during burn-induced inflammation. The research work has potential impact on the development of surgical or medical interventions against gut barrier injury in VA patients with trauma or inflammatory diseases.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
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Special Emphasis Panel (ZRD1)
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James A. Haley VA Medical Center
United States
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Haines, R J; Wang, C Y; Yang, C G Y et al. (2017) Targeting palmitoyl acyltransferase ZDHHC21 improves gut epithelial barrier dysfunction resulting from burn-induced systemic inflammation. Am J Physiol Gastrointest Liver Physiol 313:G549-G557
Beard Jr, Richard S; Yang, Xiaoyuan; Meegan, Jamie E et al. (2016) Palmitoyl acyltransferase DHHC21 mediates endothelial dysfunction in systemic inflammatory response syndrome. Nat Commun 7:12823
Breslin, Jerome W; Daines, Dayle A; Doggett, Travis M et al. (2016) Rnd3 as a Novel Target to Ameliorate Microvascular Leakage. J Am Heart Assoc 5:e003336
Haines, R J; Beard Jr, R S; Chen, L et al. (2016) Interleukin-1? Mediates ?-Catenin-Driven Downregulation of Claudin-3 and Barrier Dysfunction in Caco2 Cells. Dig Dis Sci 61:2252-61
Guo, Mingzhang; Yuan, Sarah Y; Frederich, Bert J et al. (2012) Role of non-muscle myosin light chain kinase in neutrophil-mediated intestinal barrier dysfunction during thermal injury. Shock 38:436-43