Thermal injury represents a common form of trauma associated with significant mortality and morbidity. Despite the remarkable improvements in critical care and wound management, end-organ effects of systemic inflammatory reactions characteristic of multiple organ edema and dysfunction remain life-threatening problems in patients with major burns. Of great concern is the development of microvascular barrier dysfunction, a fundamental cellular process underlying inflammatory edema that has yet to be understood at the molecular level. The overall goal of this project is to identify key signaling molecules and structural components responsible for the microvascular hyperpermeability response to thermal trauma. Within this context, a major hypothesis is developed stating that Src tyrosine kinase-signaled endothelial cytoskeletal contraction and junctional disorganization induce microvascular barrier dysfunction during thermal injury. Correspondingly, four specific aims will be achieved: 1) to characterize burn-induced microvascular leakage; 2) to examine the mechanism by which endothelial cytoskeletal contraction causes microvascular hyperpermeability; 3) to elucidate the role of VE-cadherin junctional disorganization in mediating endothelial barrier dysfunction; and 4) to verify the common signaling role of Src in the regulation of cytoskeletal and junctional structure and function. The study will test the hypotheses using a clinically relevant rat model of scald burn in combination with pharmacological approaches and molecular biology techniques. The study will provide new insights into the cellular and molecular control of endothelial barrier function. Information derived from this study will enhance our knowledge on microvascular pathobiology of not only burns but also other types of injuries associated with inflammatory responses. Furthermore, identification of signaling or structural molecules directly responsible for microvascular hyperpermeability should lead to the development of new therapeutic targets specific to the injurious process.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
Project #
Application #
Study Section
Surgery, Anesthesiology and Trauma Study Section (SAT)
Program Officer
Somers, Scott D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of California Davis
Schools of Medicine
United States
Zip Code
Meegan, Jamie E; Yang, Xiaoyuan; Beard Jr, Richard S et al. (2018) Citrullinated histone 3 causes endothelial barrier dysfunction. Biochem Biophys Res Commun 503:1498-1502
Alves, Natascha G; Trujillo, Andrea N; Breslin, Jerome W et al. (2018) Sphingosine-1-Phosphate Reduces Hemorrhagic Shock and Resuscitation-Induced Microvascular Leakage by Protecting Endothelial Mitochondrial Integrity. Shock :
Alves, Natascha G; Yuan, Sarah Y; Breslin, Jerome W (2018) Sphingosine-1-phosphate protects against brain microvascular endothelial junctional protein disorganization and barrier dysfunction caused by alcohol. Microcirculation :e12506
Doggett, Travis M; Alves, Natascha G; Yuan, Sarah Y et al. (2017) Sphingosine-1-Phosphate Treatment Can Ameliorate Microvascular Leakage Caused by Combined Alcohol Intoxication and Hemorrhagic Shock. Sci Rep 7:4078
Meegan, Jamie E; Yang, Xiaoyuan; Coleman, Danielle C et al. (2017) Neutrophil-mediated vascular barrier injury: Role of neutrophil extracellular traps. Microcirculation 24:
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
Rigor, Robert R; Shen, Qiang; Pivetti, Christopher D et al. (2013) Myosin light chain kinase signaling in endothelial barrier dysfunction. Med Res Rev 33:911-33
Yuan, Sarah Y; Shen, Qiang; Rigor, Robert R et al. (2012) Neutrophil transmigration, focal adhesion kinase and endothelial barrier function. Microvasc Res 83:82-8
Lee, Eugene S; Van Spyk, Elyse N; Chun, Kevin C et al. (2012) Monocytic adhesion molecule expression and monocyte-endothelial cell dysfunction are increased in patients with peripheral vascular disease versus patients with abdominal aortic aneurysms. J Surg Res 177:373-81

Showing the most recent 10 out of 21 publications