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%的脓毒症病例始于 作为肺部感染，导致无法控制的炎症和血管屏障的破坏。 这些过程直接涉及血管内皮细胞。尽管最近在以下方面取得了进展 了解病原体引起的血管通透性和炎症的基础， 对推动微血管完整性恢复的内在机制的不完全理解 和器官功能，是克服ALI和 败血症。因此，进一步研究确定可能的干预措施的具体机制 促进炎性损伤后血管内皮细胞屏障的修复 非常需要。这项翻译研究将检验RAS的一种新的假设机制-- 在细菌性肺损伤模型中，Rapate-1(Rap1)GTP酶辅助血管恢复。 我们假设RAP1诱导肺微血管内皮细胞连接的重新组装和 细胞连接相关螺旋卷曲蛋白(JACOP)的募集。这一过程刺激了 Jacop与RhoA GTPase特异性的鸟嘌呤核苷酸交换因子gef-H1的相互作用， 导致血管内皮细胞屏障内环境生长因子-H1活性的抑制和RhoA途径的减弱 破坏和发炎。基于这一机制，我们将确定Jacop域 并检测其抑制肿瘤细胞生长的作用。 金黄色葡萄球菌引起的局部内皮细胞高通透性和炎症 细菌微粒。拟议的研究可能会对以下方面产生更广泛的影响 细胞黏附介导的血管对炎性或促血管生成刺激的反应 结构(即白细胞的黏附和迁移，动脉粥样硬化斑块的形成， 心肌缺血/再灌流时EC屏障受损和炎性损伤等)。 一种新的依赖Rap1的局部Rho调控机制的表征 Jacop轴将增强对推动肺自我恢复和反馈机制的理解 推进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.