How Tetraspanins Regulate Sepsis

四跨膜蛋白如何调节脓毒症

• 批准号: 10654676
• 负责人: XIN A ZHANG
• 金额: $ 29万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10654676
• 关键词: Affect; Animals; Blood Cells; Blood Vessels; C-terminal; Cause of Death; Cell Adhesion Molecules; Cell membrane; Cysteine; Cytoplasmic Tail; Cytosol; Disease; E-Selectin; Endothelial Cells; Endothelium; Endotoxins; Event; Exocytosis; Extravasation; Functional disorder; Goals; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; KAI1 gene; Knockout Mice; Knowledge; Leukocytes; Lipopolysaccharides; Mediating; Membrane; Molecular; Molecular Target; Morbidity - disease rate; Multivesicular Body; Organism; Patients; Proteins; Recovery; Role; Sepsis; Signaling Molecule; Sorting; Stimulus; Structure; Surface; TNF gene; Testing; Thrombosis; Transmembrane Domain; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vesicle; animal mortality; cadherin 5; cytokine; disulfide bond; exosome; extracellular; glycosylation; improved; in vivo; insight; mortality; new therapeutic target; palmitoylation; rab GTP-Binding Proteins; recruit; response; septic; septic patients; trafficking; Affect; Animals; Blood Cells; Blood Vessels; C-terminal; Cause of Death; Cell Adhesion Molecules; Cell membrane; Cysteine; Cytoplasmic Tail; Cytosol; Disease; E-Selectin; Endothelial Cells; Endothelium; Endotoxins; Event; Exocytosis; Extravasation; Functional disorder; Goals; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Injury; KAI1 gene; Knockout Mice; Knowledge; Leukocytes; Lipopolysaccharides; Mediating; Membrane; Molecular; Molecular Target; Morbidity - disease rate; Multivesicular Body; Organism; Patients; Proteins; Recovery; Role; Sepsis; Signaling Molecule; Sorting; Stimulus; Structure; Surface; TNF gene; Testing; Thrombosis; Transmembrane Domain; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vesicle; animal mortality; cadherin 5; cytokine; disulfide bond; exosome; extracellular; glycosylation; improved; in vivo; insight; mortality; new therapeutic target; palmitoylation; rab GTP-Binding Proteins; recruit; response; septic; septic patients; trafficking

Vascular inflammatory responses determine the onset, progression, and consequence of sepsis. Tetraspanin CD82 proteins are expressed in endothelial cells (ECs) and leukocytes. Our recent study revealed that CD82 facilitates vascular inflammatory responses during sepsis. We demonstrated that, to facilitate inflammation, endothelial CD82 promotes lipopolysaccharide (LPS)- induced vascular leakage, leukocyte recruitment, and endothelial release of cytokines, leading to marked increase in mortality of animal with sepsis. How CD82 promotes the inflammatory events in blood vessels during sepsis is unclear. The goal of this study is to identify the mechanisms by which CD82 facilitates vascular inflammatory responses in sepsis at the molecular, cellular, and organism levels. We hypothesize that, CD82 facilitates the vesicular trafficking of inflammation-related molecules such as VE- cadherin, E-selectin, and cytokines, to promote inflammatory responses in sepsis and therefore exacerbate sepsis. In this project, we will first determine how CD82 inhibits vascular stability in sepsis by assessing the regulatory roles of CD82 in i) inflammation-induced disruption of EC-EC contacts/junctions and ii) recovery of endothelial barriers from the disrupted EC-EC contacts/junctions. Secondly, we will determine the mechanism by which CD82 promotes vascular recruitment of leukocytes during sepsis by assessing CD82 effects on the i) levels, ii) activities, and iii) turnover of inflammation- related cell adhesion proteins in ECs and leukocytes during sepsis. Finally, we will determine how CD82 inhibits cytokine secretion in sepsis by i) assessing in vivo and in vitro effects of CD82 on cytokine secretomes, ii) revealing CD82 roles in exosome formation and exocytosis, and iii) identifying the Rab GTPase(s) crucial for CD82-regulated exocytosis. This project will fill important knowledge gaps for the regulatory mechanisms of vascular inflammatory events in response to septic injury, leading to systemic vascular dysfunction, at the molecular, cellular, and organism levels. This project will also establish CD82 as a novel therapeutic target for ameliorating systemic vascular dysfunction during sepsis and improving the survival of sepsis patients.

血管炎症反应决定了开始，进展和后果 败血症。四叠蛋白CD82蛋白在内皮细胞（ECS）和白细胞中表达。我们的 最近的研究表明，CD82促进败血症期间的血管炎症反应。我们 证明，为了促进炎症，内皮CD82促进脂多糖（LPS） - 诱导的血管泄漏，白细胞募集和细胞因子的内皮释放，导致 败血症的动物死亡率明显增加。 CD82如何促进炎症事件 败血症期间的血管尚不清楚。 这项研究的目的是确定CD82促进血管的机制 分子，细胞和生物体水平的败血症的炎症反应。我们假设 CD82促进了与炎症相关分子（例如VE-）的囊泡运输 钙粘蛋白，电子 - 选择素和细胞因子，以促进败血症的炎症反应，因此 恶化败血症。 在这个项目中，我们将首先确定CD82如何通过评估败血症的血管稳定性 CD82在i）炎症引起的EC-EC接触/交界处的破坏和 ii）从中断的EC-EC触点/交界处回收内皮屏障。其次，我们会的 确定CD82促进白细胞血管募集的机制 败血症通过评估CD82对I）水平的影响，ii）活动，ii）炎症流失 - 败血症期间EC和白细胞中的相关细胞粘附蛋白。最后，我们将确定如何 CD82通过i）评估CD82的体内和体外作用来抑制败血症的细胞因子分泌 细胞因子秘密组，ii）揭示了CD82在外泌体形成和胞吐作用中的作用，iii） 确定RAB GTPase（S）对于CD82调节的胞吐作用至关重要。 该项目将填补重要的知识空白 在败血性损伤时炎症事件，导致全身血管功能障碍，在 分子，细胞和生物水平。这个项目还将建立CD82作为小说 败血症期间改善全身血管功能障碍的治疗靶点 败血症患者的生存。