Effects of Histones, Polyphosphates, and Thrombin on Native Endothelum in Trauma
Hypothesis: Excess histones, polyP, and proinflammatory cytokines(e.g. interleukin-6), released into the plasma of trauma patients, drive a common pathway of endothelial dysfunction involving TRPV4 channel activation and Ca2+ overload. The resulting endothelial dysfunction alters microvascular reactivity to thrombin and impairs thrombomodulin/protein C activation, contributing to coagulopathy and multi-organ failure after trauma.
Aim 1: We will elucidate the molecular basis of Ca2+ overload in native endothelium exposed to histones and polyP.
Aim 2: We will determine the impact of histone and/or polyP-mediated EC Ca2+ on endothelial-dependent dilation and vascular permeability in intact arteries.
Aim 3: We will characterize thrombin-thrombomodulin interactions on the endothelial surface of microvascular cerebral, pulmonary,and mesenteric arteries, after trauma.
Aim 4: We will determine the impact of blocking histones andpolyP in vitro and in vivo after trauma, on restoration of microvascular endothelial function.
Last modified January 03 2014 11:15 AM