Control of septic inflammation and lung microvascular endothelial barrier by cell junction signaling nexus

点击翻译按钮获取中文摘要

Sepsis remains a major cause of morbidity and mortality. Typically, 50% of all sepsis cases start as an infection in the lungs leading to uncontrolled inflammation and breach of vascular barrier. These processes directly involve vascular endothelial cells. Despite the recent progress towards understanding of the basis of pathogen-induced vascular permeability and inflammation, incomplete understanding of intrinsic mechanisms driving recovery of microvascular integrity and organ function, represents a critical barrier to progress beyond the problem of ALI and sepsis. Therefore, further studies identifying specific mechanisms potential interventions accelerating vascular endothelial cell (EC) barrier restoration after inflammatory insults are much needed. This translational research study will test a new hypothetical mechanism of Ras- proximate-1 (Rap1) GTPase-assisted vascular recovery in the models of bacterial lung injury. We hypothesize that Rap1-induces re-assembly of lung microvascular EC cell junctions and recruitment of cell junction-associated coiled-coil protein (JACOP). This process stimulates JACOP interaction with RhoA GTPase-specific guanine nucleotide exchange factor GEF-H1, leading to inhibition of GEF-H1 activity, and attenuation of RhoA pathway of EC barrier disruption and inflammation. Based on this mechanism, we will determine JACOP domains with GEF-H1 inhibitory and cell junction targeting activities and test their efficacy in suppressing the local endothelial hyper-permeability and inflammation caused by Staphylococcus aureus bacterial particles. The proposed study may have a broader impact on the other aspects of vascular responses to inflammatory or pro-angiogenic stimuli mediated by cell adhesive structures (i.e. adhesion and transmigration of leukocytes, formation of atherosclerotic plaque, EC barrier compromise and inflammatory injury during cardiac ischemia/reperfusion, etc.). Characterization of a new Rap1-dependent mechanism of local Rho control by GEF-H1 - JACOP axis will enhance understanding of feedback mechanisms driving lung self-recovery and advance development of future therapeutic treatments.