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

• 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
• 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

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.

败血症仍然是发病率和死亡率的主要原因。通常，所有败血症病例中有50％开始 作为肺部感染，导致不受控制的炎症和违反血管屏障。 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， 对促进微血管完整性恢复的内在机制的不完全理解 和器官功能，代表了超出Ali和Ali问题的关键障碍 败血症。因此，进一步的研究确定特定机制潜在的干预措施 炎症性损伤后加速的血管内皮细胞（EC）屏障恢复是 非常需要。这项翻译研究将测试RAS-的新假设机制 在细菌肺损伤模型中，近端1（RAP1）GTPase辅助的血管恢复。 我们假设Rap1-引起肺微血管EC细胞连接和 细胞连接相关盘绕蛋白（JACOP）的募集。这个过程刺激了 JACOP与RhoA GTPase特异性鸟嘌呤核苷酸交换因子GEF-H1相互作用， 导致抑制GEF-H1活性，并衰减EC屏障的RhoA途径 破坏和炎症。基于此机制，我们将确定Jacop域 GEF-H1抑制性和细胞连接靶向活动，并测试其抑制功效 金黄色葡萄球菌引起的局部内皮过度渗透性和炎症 细菌颗粒。拟议的研究可能对 细胞粘合剂介导的炎症或前血管生成刺激的血管反应 结构（即白细胞的粘附和移民，动脉粥样硬化斑块的形成， EC障碍和心脏缺血/再灌注期间的炎症损伤等）。 GEF-H1的局部RHO控制的新的RAP1依赖机制的表征 雅各布轴将增强对推动肺自我恢复和的反馈机制的理解 提前发展未来的治疗疗法。