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

脓毒症仍然是发病率和死亡率的主要原因。通常，50%的败血症病例开始于 肺部感染导致不受控制的炎症和血管屏障破裂。 这些过程直接涉及血管内皮细胞。尽管最近取得了进展， 了解病原体诱导的血管通透性和炎症的基础， 不完全理解驱动微血管完整性恢复的内在机制 和器官功能，是超越ALI问题的关键障碍， 败血症因此，进一步的研究确定具体机制的潜在干预措施， 炎症损伤后加速血管内皮细胞（EC）屏障的恢复， 非常需要。这项转化研究将测试Ras的一种新的假设机制， 细菌性肺损伤模型中近端-1（Rap 1）GTP酶辅助血管恢复。 我们假设Rap 1诱导肺微血管EC细胞连接的重新组装， 募集细胞连接相关卷曲螺旋蛋白（JACOP）。这个过程刺激了 JACOP与RhoA GTP酶特异性鸟嘌呤核苷酸交换因子GEF-H1的相互作用， 导致GEF-H1活性的抑制和EC屏障的RhoA途径的减弱 破坏和炎症。基于这种机制，我们将使用 GEF-H1抑制和细胞连接靶向活性，并测试它们在抑制细胞凋亡中的功效。 金黄色葡萄球菌引起的局部内皮细胞高通透性和炎症 细菌颗粒拟议的研究可能会对其他方面产生更广泛的影响， 细胞粘附剂介导的炎症或促血管生成刺激的血管反应 结构（即白细胞的粘附和迁移，动脉粥样硬化斑块的形成， EC屏障受损和心脏缺血/再灌注期间的炎性损伤等）。 GEF-H1对Rap 1依赖的局部Rho调控机制的表征 JACOP轴将增强对驱动肺自我恢复的反馈机制的理解， 推动未来治疗方法的发展。

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.