How Tetraspanins Regulate Sepsis

四跨膜蛋白如何调节脓毒症

• 批准号: 10437734
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10437734
• 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; Molecular; Molecular Target; Morbidity - disease rate; Multivesicular Body; Organism; Patients; Proteins; Recovery; Role; Sepsis; Signaling Molecule; Sorting - Cell Movement; Stimulus; Structure; Surface; TNF gene; Testing; Thrombosis; Transmembrane Domain; Vascular Cell Adhesion Molecule-1; Vascular Diseases; Vesicle; animal mortality; base; cadherin 5; cytokine; disulfide bond; exosome; extracellular; improved; in vivo; insight; mortality; new therapeutic target; 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炎症的发生、发展和后果， 败血症四跨膜蛋白CD 82蛋白在内皮细胞（EC）和白细胞中表达。我们 最近的研究表明，CD 82促进脓毒症期间的血管炎症反应。我们 表明，为了促进炎症，内皮CD 82促进脂多糖（LPS）- 诱导血管渗漏、白细胞募集和内皮细胞因子释放，导致 败血症动物死亡率显著增加。CD 82如何促进炎症反应 脓毒症期间的血管尚不清楚。 本研究的目的是确定CD 82促进血管生成的机制。 脓毒症的炎症反应在分子、细胞和生物体水平。我们假设 CD 82促进炎症相关分子如VE-1的囊泡运输。 钙粘蛋白、E-选择素和细胞因子在脓毒症中促进炎症反应， 加重败血症 在这个项目中，我们将首先通过评估CD 82如何抑制脓毒症中的血管稳定性来确定， CD 82在i）炎症诱导的EC-EC接触/连接破坏和 ii）从破坏的EC-EC接触/连接恢复内皮屏障。其次，我们将 确定CD 82促进白细胞在血管中募集的机制， 通过评估CD 82对炎症的i）水平、ii）活性和iii）转换的影响， 脓毒症期间内皮细胞和白细胞中的相关细胞粘附蛋白。最后，我们将确定如何 CD 82通过以下方式抑制脓毒症中的细胞因子分泌： 细胞因子分泌组，ii）揭示CD 82在外泌体形成和胞吐作用中的作用，和iii） 鉴定对CD 82调节的胞吐作用至关重要的Rab GT3。 该项目将填补血管调节机制的重要知识空白 脓毒性损伤引起的炎症事件，导致全身血管功能障碍， 分子、细胞和生物体水平。这个项目也将建立CD 82作为一个新的 用于改善脓毒症期间全身血管功能障碍和改善 脓毒症患者的生存率。