Endothelial Cell Deubiquitinase A20 Signals Repair of Lung Vascular Injury

内皮细胞去泛素酶 A20 发出肺血管损伤修复信号

基本信息

批准号：
9301023
负责人：
CHINNASWAMY TIRUPPATHI
金额：
$ 39.98万
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：
2015
资助国家：
美国
起止时间：
2015-07-01 至 2019-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9301023
关键词：
Acute Acute Lung Injury Address Adherens Junction Attenuated Biochemical Blood Vessels Blood capillaries Cause of Death Cells Complex Data Disease Edema Endothelial Cells Endotoxins Enzymes Extravasation Feedback Genetic Genetic Models Genetic Transcription Homeostasis Image Infiltration Inflammation Inflammatory Investigation Knock-out Leukocytes Liquid substance Lung Mediating Modeling Molecular Motion Mus Permeability Physiological Positioning Attribute Procollagen-Proline Dioxygenase Protein Tyrosine Phosphatase Proteins Pulmonary Edema Regulation Resolution Role Sepsis Signal Pathway Signal Transduction Structure of parenchyma of lung TLR4 gene TRAF6 gene Testing Therapeutic Ubiquitin United States Vascular Permeabilities base cadherin 5 capillary lung injury lung repair lung vascular injury mouse model neutrophil new therapeutic target novel overexpression prevent public health relevance restoration trafficking

项目摘要

DESCRIPTION (provided by applicant): Acute lung injury (ALI) is a complex inflammatory disease associated with increased lung vascular permeability and formation of protein-rich edema fluid and an infiltration of inflammatory cells in lung tissue and airspace. Reassembly of lung vascular endothelial adherens junctions (AJs) is a critical factor contributing to resolution f acute inflammatory lung injury. Expression of vascular endothelial (VE)-cadherin and the interacting endothelial protein tyrosine phosphatase (VE-PTP) at AJs is vital for endothelial barrier integrity. However, the signaling mechanisms that mediate the reassembly of endothelial AJs are poorly understood. We have identified in a genetic model of endothelial cell (EC)-restricted A20 (Tnfaip3) knockout (A20ΔEC) mice, the novel role of the ubiquitin editing function of A20 in regulating expression of VE-cadherin and VE-PTP at AJs. We made the following key observations (Supporting Data): (i) A20ΔEC mice displayed markedly reduced expression of VE- cadherin and VE-PTP at AJs; (ii) VE-cadherin and VE-PTP expression was not restored at AJs of A20ΔEC mice after endotoxin challenge; (iii) A20ΔEC mice showed persistent prolyl hydroxylase 2 (PHD2) expression and defective HIF2α expression post-endotoxin challenge. Based on these novel observations, in Aim 1, we will test the hypothesis that expression of A20 in lung ECs, downstream of TLR4 signaling, promotes the sequestration of VE-cadherin at AJs, and thus is a central feedback mechanism for stabilizing endothelial barrier and promoting resolution of lung injury. In Aim 2, we will test the hypothesis that EC-expressed A20 serves a pro-resolution function in inflammatory lung injury by down-regulating PHD2 to stabilize HIF2α and transcriptionally regulating VE-PTP expression so as to strengthen VE-cadherin function at AJs. With a better understanding of the signaling mechanisms of A20 function in lung endothelial cells, we will be in a position to identify therapeutic strategies that can target A20 function and thereby restore endothelial barrier integrity to resolve inflammatory lung injury.

描述（由申请人提供）：急性肺损伤（ALI）是一种复杂的炎症性疾病，与肺血管通透性增加、富含蛋白质的水肿液的形成以及肺组织和气腔中炎症细胞的浸润相关。连接（AJ）是解决急性炎症性肺损伤的关键因素，血管内皮（VE）-钙粘蛋白的表达及其相互作用。 AJ 上的内皮蛋白酪氨酸磷酸酶 (VE-PTP) 对于内皮屏障的完整性至关重要，然而，我们在内皮细胞 (EC) 限制性 A20 的遗传模型中对介导内皮 AJ 重组的信号机制知之甚少。 (Tnfaip3)敲除(A20ΔEC)小鼠，A20泛素编辑功能在调节中的新作用我们进行了以下关键观察（支持数据）：（i）A20ΔEC 小鼠 AJ 处 VE-钙粘蛋白和 VE-PTP 的表达显着降低；内毒素攻击后，A20ΔEC 小鼠 AJ 处的 VE-PTP 表达未恢复；(iii) A20ΔEC 小鼠表现出持久的脯氨酰基；内毒素攻击后羟化酶 2 (PHD2) 表达和缺陷 HIF2α 表达基于这些新的观察结果，在目标 1 中，我们将测试肺 EC 中 A20 的表达（TLR4 信号下游）促进 VE-钙粘蛋白的隔离的假设。在 AJ 处，因此是稳定内皮屏障和促进肺损伤消退的中央反馈机制。在目标 2 中，我们将检验以下假设： EC 表达的 A20 通过下调 PHD2 以稳定 HIF2α 并转录调节 VE-PTP 表达，从而增强 AJ 处的 VE-钙粘蛋白功能，从而在炎症性肺损伤中发挥促消退作用。肺内皮细胞的功能，我们将能够确定针对 A20 功能和从而恢复内皮屏障完整性，解决炎症性肺损伤。