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Targeting Latexin Signaling for Endothelial Barrier Dysfunction in Inflammatory Lung Injury

靶向乳胶蛋白信号传导治疗炎症性肺损伤中的内皮屏障功能障碍

基本信息

批准号：
10457247
负责人：
Ross S Summer
金额：
$ 64.89万
依托单位：
THOMAS JEFFERSON UNIVERSITY
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：
2021-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10457247
关键词：
Accounting Acute Lung Injury Acute Respiratory Distress Syndrome Adherens Junction Agonist Alveolar Attenuated Automobile Driving Bacterial Pneumonia Behavior Binding Biological Availability Biology Blood Platelets Blood Vessels Blood flow Cells Cessation of life Clathrin Coagulation Process Complex Critical Illness Data Data Set Development Diabetes Mellitus Edema Endocytosis Endothelial Cells Endothelium Enzymes Exocytosis Experimental Models Exposure to Extravasation Floods Fostering Functional disorder Genes Goals Grant Human In Situ In Vitro Inflammation Inflammatory Injury Investigation Knockout Mice Knowledge Laboratories Lead Length of Stay Link Lipopolysaccharides Lung Mass Spectrum Analysis Mediating Membrane Modeling Molecular Morbidity - disease rate Mus Obesity Organ PC3.1 antigen Pathogenesis Pathogenicity Pathologic Pharmacology Phosphorylation Plasma Platelet Activation Play Proteins Pulmonary Edema Pulmonary Inflammation Respiratory Failure Role S-nitro-N-acetylpenicillamine SNAP receptor Sepsis Severities Signal Transduction Testing The Sun Thrombosis Time Up-Regulation Vascular Diseases cadherin 5 design endothelial dysfunction enhancer-binding protein AP-2 gain of function hypercholesterolemia in vivo innovation insight interest interstitial knock-down lung injury microbial mortality mouse model novel novel strategies novel therapeutic intervention organ injury prevent pulmonary vascular disorder respiratory response shear stress src-Family Kinases syntaxin 3 thrombotic complications tool trafficking transcriptome sequencing translational progress von Willebrand Factor

项目摘要

Project Summary The Acute Respiratory Distress Syndrome (ARDS) is a common cause of respiratory failure in the critically ill, accounting for ~75000 deaths/year and 3.6 million hospital days. The existing paradigm is that the ARDS results from widespread dysfunction of the pulmonary endothelium, leading to microvascular thrombosis, interstitial edema, alveolar flooding and respiratory failure, although the mechanisms leading to endothelial dysfunction remain unknown. This proposal arises from novel observations linking the upregulation of Latexin to endothelial dysfunction in the lung. We found that healthy lung endothelium expresses low levels of Latexin whereas levels markedly increase in response to turbulent flow or bacterial LPS. Further, we found that endothelial barrier function was enhanced by reducing Latexin expression in LPS-exposed lung endothelial cells and that global deficiency of Latexin in mice reduced LPS-induced pulmonary edema, lung inflammation and mortality. Mechanistically, we found that Latexin mediated its effects through complex mechanisms, including binding to the enzyme Src kinase and facilitating its membrane translocation and phosphorylation of VE-cadherin at adherens junctions (AJ). Additionally, mass spectroscopy revealed that Latexin physically interacts with several other proteins, including clathrin and AP2, suggesting a role in endocytic trafficking, and syntaxin-3 and SNAP3, suggesting a role in exocytosis. Consistent with this latter mechanism, we found that Latexin deficiency reduced von Willenbrand factor secretion from lung endothelium. Taken together, these observations lead us to propose the following central hypothesis regarding the role of Latexin in lung endothelial biology and the pathogenesis of endothelial dysfunction in ARDS. We hypothesize that Latexin plays a pathogenic role in driving agonist- induced endothelial dysfunction in the lung and that inhibiting its interactions with other key proteins will reduce the severity of pulmonary edema, lung inflammation and microvascular thrombotic complications in experimentally-induced ARDS. To test this hypothesis, we propose 3 independent but mechanistically linked Specific Aims. In Aim 1, we will establish that endothelial-specific deletion of Latexin enhances endothelial barrier protection and reduces microvascular thrombosis and mortality to LPS in mice. In Aim 2, we will delineate the molecular mechanisms by which Latexin regulates VE-cadherin membrane bioavailability at endothelial AJs by performing various in vitro and in vivo loss- and gain-of-function studies for genes linked to Src-mediated VE-cadherin phosphorylation and clathrin-mediated endocytosis in ECs. In Aim 3, we will delineate the molecular mechanisms by which Latexin mediates vWF secretion from endothelial cells, focusing on its role in SNARE complex formation. In toto, this proposal will establish the mechanisms by which Latexin regulates key pathological behaviors in lung endothelium and provide direction for developing novel therapeutic approaches for inflammatory vascular diseases of the lung, such as the ARDS.

项目总结