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

通过细胞连接信号连接控制化脓性炎症和肺微血管内皮屏障

基本信息

批准号：
10631107
负责人：
Anna Birukova
金额：
$ 56.31万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-01 至 2025-05-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10631107
关键词：
Abdomen Acceleration Acute Adhesions Adhesives Advanced Development Agonist Antibiotic Therapy Arterial Fatty Streak Automobile Driving Bacterial Model Blood Vessels Cell Adhesion Cells Clinical Coagulation Process Data Development Disease Edema Endothelial Cells Endothelium Extravasation Feedback Functional disorder Future Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Incidence Infection Inflammation Inflammatory Injury Intercellular Junctions Intervention Leukocytes Lung Mediating Microtubules Molecular Monomeric GTP-Binding Proteins Morbidity - disease rate Multiple Organ Failure Myocardial Ischemia Organ Pathologic Pathologic Processes Pathway interactions Peripheral Permeability Pre-Clinical Model Process Proteins Pulmonary Inflammation Recovery Regulation Reperfusion Therapy Role Sepsis Signal Transduction Source Staphylococcus aureus Sterility Stimulus Structure TNF gene Tertiary Protein Structure Testing Therapeutic Thrombin Translational Research Urinary tract Vascular Endothelial Cell Vascular Endothelium Vascular Permeabilities attenuation cytokine cytokine release syndrome effective therapy experimental study improved in vivo lung injury lung microvascular endothelial cells mechanical force methicillin resistant Staphylococcus aureus migration mortality novel particle pathogen pharmacologic polypeptide pulmonary function recruit research study response restoration rho septic vascular inflammation

项目摘要

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.

脓毒症仍然是发病和死亡的主要原因。通常，50% 的败血症病例是从作为肺部感染，导致不受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。尽管最近在这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，对驱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，是解决 ALI 问题的一个关键障碍，败血症。因此，进一步研究确定潜在干预措施的具体机制加速炎症损伤后血管内皮细胞 (EC) 屏障的恢复非常需要。这项转化研究将测试 Ras- 的新假设机制 proximate-1 (Rap1) GTPase 在细菌性肺损伤模型中辅助血管恢复。我们假设 Rap1 诱导肺微血管 EC 细胞连接的重新组装，并且细胞连接相关卷曲螺旋蛋白（JACOP）的募集。这个过程刺激 JACOP 与 RhoA GTPase 特异性鸟嘌呤核苷酸交换因子 GEF-H1 相互作用，导致 GEF-H1 活性受到抑制，EC 屏障的 RhoA 通路减弱破坏和炎症。基于这个机制，我们将确定JACOP域 GEF-H1 抑制和细胞连接靶向活性并测试其抑制效果金黄色葡萄球菌引起的局部内皮渗透性过高和炎症细菌颗粒。拟议的研究可能会对其他方面产生更广泛的影响细胞粘合剂介导的血管对炎症或促血管生成刺激的反应结构（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/再灌注期间的炎症损伤等）。 GEF-H1 局部 Rho 控制的新 Rap1 依赖性机制的表征 - JACOP 轴将增强对驱动肺自我恢复的反馈机制的理解推进未来治疗的发展。