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

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.

血管炎症反应决定血管病变的发生、发展和后果。 败血症。Tetraspanin CD82蛋白表达于内皮细胞和白细胞。我们的 最近的研究表明，CD82促进了脓毒症时的血管炎症反应。我们 研究表明，为了促进炎症，内皮细胞CD82促进内毒素- 诱导血管渗漏、白细胞募集和内皮细胞因子释放，导致 脓毒症动物死亡率显著增加。CD82是如何促进炎症反应的 脓毒症期间的血管情况尚不清楚。 这项研究的目的是确定CD82促进血管生成的机制 脓毒症在分子、细胞和机体水平的炎症反应。我们假设 CD82促进炎症相关分子的囊泡运输，如VE- 钙粘附素、E-选择素和细胞因子促进脓毒症的炎症反应 加重败血症。 在这个项目中，我们将首先通过评估CD82在脓毒症中如何抑制血管稳定性来确定 CD82在炎症诱导的EC-EC接触/连接的破坏和 二)从破裂的EC-EC接触/连接中恢复内皮屏障。其次，我们将 确定CD82促进白细胞血管募集的机制 通过评估CD82对I)水平、II)活动和III)炎症周转的影响来评估脓毒症 脓毒症时内皮细胞和白细胞中的相关细胞黏附蛋白。最后，我们将确定如何 CD82抑制脓毒症细胞因子分泌的实验研究 细胞因子分泌体，ii)揭示CD82在外切体形成和胞吐作用中的作用，以及iii) 确定CD82调节胞吐作用的关键基因Rab GTP酶(S)。 该项目将填补血管调节机制方面的重要知识空白。 脓毒症损伤后的炎症事件，导致全身血管功能障碍 分子、细胞和生物体水平。该项目还将把CD82确立为一部小说 改善脓毒症时全身血管功能障碍的治疗靶点 脓毒症患者的生存。

项目成果

EWI2 promotes endolysosome-mediated turnover of growth factor receptors and integrins to suppress lung cancer.

EWI2促进了内溶性介导的生长因子受体和整合素的周转率，以抑制肺癌。

• DOI: 10.1016/j.canlet.2022.215641
• 发表时间: 2022-06-28
• 期刊: CANCER LETTERS
• 影响因子: 9.7
• 作者: Wang, Jie;Wren, Jonathan D.;Ding, Yingjun;Chen, Junxiong;Mittal, Nikhil;Xu, Chao;Li, Xing;Zeng, Cengxi;Wang, Meng;Shi, Jing;Zhang, Yanhui H.;Han, Sangyoon J.;Zhang, Xin A.
• 通讯作者: Zhang, Xin A.

A Bioinformatics Perspective on the Links Between Tetraspanin-Enriched Microdomains and Cardiovascular Pathophysiology.

• DOI: 10.3389/fcvm.2021.630471
• 发表时间: 2021
• 期刊: Frontiers in cardiovascular medicine
• 影响因子: 3.6
• 作者: Sun G;Chen J;Ding Y;Wren JD;Xu F;Lu L;Wang Y;Wang DW;Zhang XA
• 通讯作者: Zhang XA