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Endothelial TAK1 Signaling and Resolution of Pulmonary Edema in Sepsis

脓毒症肺水肿的内皮 TAK1 信号转导和解决

基本信息

批准号：
9535680
负责人：
CHINNASWAMY TIRUPPATHI
金额：
$ 4.55万
依托单位：
UNIVERSITY OF ILLINOIS AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-01 至 2020-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9535680
关键词：
Actins Acute Lung Injury Address Adherens Junction Albumins Binding Biochemical Blood Vessels Cadherins Calcium Calmodulin Cause of Death Cell surface Coagulation Process Complex Coupled Data Defect Disease Dissociation Edema Endoplasmic Reticulum Endothelial Cells Exhibits Extravasation Feedback Felis catus G-Protein-Coupled Receptors Genes Genetic Models Glycogen Synthase Kinases Image Inflammation Mediators Inflammatory Investigation Knock-out Knockout Mice Lung MAP3K7 gene Measurement Mediating Mediator of activation protein Membrane Modeling Mus PAR-1 Receptor Pathway interactions Patients Peptide Hydrolases Permeability Phosphorylation Phosphotransferases Physiological Play Prevention Process Proteins Pulmonary Edema Recovery Regulation Resolution Role STIM1 gene Secondary to Sepsis Signal Pathway Signal Transduction Tamoxifen Testing Therapeutic Agents Thrombin Transforming Growth Factors Ubiquitin Ubiquitination Vascular Permeabilities alpha catenin base beta catenin beta-Transducin Repeat-Containing Proteins cadherin 5 effective therapy glycogen synthase kinase 3 beta in vivo lung injury mouse model novel novel strategies novel therapeutic intervention prevent public health relevance repaired response sensor ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): Sepsis associated with acute lung injury (ALI) is a common cause of death in hospitalized patients. ALI is in large part the result of lung vascular leakage and protein rich edema and there is a lack of effective therapy. Here, we have proposed a novel strategy to reverse ALI by stimulating an endogenous recovery process that is usually activated after lung injury. Thrombin, an edema-genic factor generated during sepsis, mediates pulmonary vascular leakage by activating protease-activated receptor-1 (PAR-1) on the endothelial cell surface. PAR-1-induced Ca2+ entry via store-operated Ca2+-entry channels (SOCs), disassembles endothelial adherens junctions (AJs) to cause increased lung vascular leak. An endoplasmic reticulum (ER) localized Ca2+ sensor protein stromal interacting molecule-1 (STIM1), is crucial for activating SOC to induce store- operated Ca2+-entry (SOCE) in endothelial cells (ECs). Now, we have identified in a murine model of tamoxifen-inducible endothelial cell (EC)-restricted TAK1 (Map3k7) deletion (Map3k7i∆EC), a key role for TAK1 in resolving PAR-1-mediated pulmonary edema formation through regulation of the functions of STIM1, glycogen synthase kinase-3β (GSK-3β) and β-catenin in ECs. We made the following observations (Supporting Data): i) TAK1 null ECs exhibited augmented SOCE and permeability in response to PAR-1 activation; ii) PAR-1-induced lung vascular permeability in vivo was not reversible in Map3k7i∆EC mice; iii) β- catenin expression was markedly reduced in ECs of Map3k7i∆EC mice; iv) glycogen synthase kinase-3β (GSK- 3β) was persistently active in ECs of Map3k7i∆EC mice, which may account for the markedly reduced expression of β-catenin in ECs of Map3k7i∆EC mice; v) PAR-1-medatied TAK1 activation was prevented in ECs of EC-restricted STIM1 knockout (Stim1∆EC) mice; vi) surprisingly, we observed that SOCE signals the inactivation of GSK-3β via TAK1 activation in ECs; vii) importantly, PAR-1-mediated lung vascular leak was markedly reduced in tamoxifen-inducible EC-restricted GSK-3β knockout (GSK-3βi∆EC) mice. Based on these novel observations, in Aim 1, we will test the hypothesis that TAK1 activation secondary to STIM1-mediated SOCE induces STIM1 phosphorylation which in turn inhibits SOCE and dampens lung vascular permeability. In Aim 2, we will test the hypothesis that TAK1 activation secondary to STIM1-mediated SOCE phosphorylates GSK-3β to inactivate GSK-3β, which in turn promotes increased β-catenin expression at endothelial AJs to restore endothelial barrier integrity and thereby resolves pulmonary edema. A better understanding of the signaling mechanisms of TAK1 functions downstream of SOCE will lead to novel therapeutic approaches that will resolve pulmonary edema in sepsis.