Angiopoietin/Tie signaling regulation of vascular leakage in lung inflammation

血管生成素/Tie信号传导对肺部炎症血管渗漏的调节

• 批准号: 9927927
• 负责人: Donald M McDonald
• 金额: $ 63.44万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-07-01 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927927
• 关键词: ANGPT1 gene; Acute Lung Injury; Admission activity; Adult Respiratory Distress Syndrome; Agonist; Alveolar; Alveolar Cell; Angiopoietin-2; Angiopoietins; Biological Markers; Blood; Blood Vessels; Blood capillaries; Clinical; Critical Illness; Data; Development; Disease model; Endothelial Cells; Event; Extravasation; FOXO1A gene; Feedback; Fibrinogen; Gases; Genetic; Genetic Transcription; Impairment; In Vitro; Individual; Inflammation; Inflammatory; Influenza; Lead; Lung; Lung Inflammation; Maintenance; Measures; Mediating; Methods; Microspheres; Modeling; Monitor; Mus; Orphan; Outcome; Patients; Pharmacology; Phosphorylation; Pilot Projects; Plasma; Prevention; Prognostic Marker; Protein Dephosphorylation; Receptor Signaling; Regulation; Sepsis; Severities; Severity of illness; Signal Pathway; Signal Transduction; Site; Stimulus; TIE-2 Receptor; Testing; Translating; Vascular Diseases; Vascular Permeabilities; Vascular remodeling; Virus Diseases; Work; airway inflammation; clinically significant; cytokine; endothelial dysfunction; experimental study; gain of function; in vivo; influenzavirus; loss of function; lung injury; lung vascular injury; mortality; mortality risk; mouse model; novel; novel strategies; overexpression; prognostic significance; receptor; vascular contributions; vascular endothelial protein tyrosine phosphatase; vascular injury

Angiopoietin/Tie signaling regulation of vascular leakage in lung inflammation PROJECT SUMMARY As a central feature of acute lung injury and acute respiratory distress syndrome (ARDS), vascular leakage not only impairs gas exchange but also initiates a cascade of events that can have fatal consequences. No treatments are currently available to reduce leakage by stabilizing the lung vasculature. This project will determine the contributions of angiopoietin-2 (Ang2), orphan receptor Tie1, and VE-PTP, also known as vascular endothelial protein-tyrosine phosphatase, to the regulation of Tie2 (Tek) receptor signaling and increased vascular permeability (“leakage”) in lung injury. Building on known anti-leakage effects of angiopoietin-1 (Ang1) and other Tie2 agonists, the project will target components of a recently described positive feedback loop that governs the severity of vascular leakage. Inflammatory cytokines that trigger Tie1 receptor ectodomain shedding and inactivation and Tie2 signaling suppression in endothelial cells also increase Foxo1 transcriptional activity and expression of Ang2, which sustains Tie2 inactivation and leakage. Aim #1 will explore new approaches for reducing leakage and promoting vascular stability in lung injury by reversing the suppression of Tie2 signaling in endothelial cells of alveolar capillaries. Experiments will determine the contributions of Ang2 overexpression, Tie1 ectodomain shedding and inactivation, and VE-PTP- mediated Tie2 dephosphorylation to Tie2 inactivation and leakage in lung injury. Genetic and pharmacologic gain- and loss-of-function strategies will be used to activate Tie2, inhibit Ang2, suppress Tie1 ectodomain shedding, and inhibit VE-PTP activity in the lung vasculature in prevention and reversal trials of sepsis and influenza virus infection in mice. Tie1, Tie2 phosphorylation, Ang2, VE-PTP, and leakage will be assessed as readouts. Leakage will be localized and measured by novel methods for visualizing extravasated fibrinogen and 20-nm fluorescent microspheres at the level of individual alveolar capillaries. Aim #2 will examine the functional and prognostic significance of elevated circulating levels of soluble Tie1 (sTie1) as a biomarker of endothelial dysfunction in lung injury. Studies in mice will identify changes in endothelial cell Tie2 signaling that lead to increased blood levels of sTie1 and how these relate to the severity of leakage from lung capillaries. Parallel studies of critically ill patients will probe the clinical significance of elevated plasma levels of sTie1 in sepsis, with or without the development of ARDS. The work will build on data from pilot studies showing 67% mortality in 23 critically ill patients with elevated plasma levels of sTie1 and Ang2 at admission, compared to only 8% in those with normal sTie1 and Ang2. Together, the experiments will define the functional benefit of activating Tie2, inhibiting Ang2, suppressing Tie1 ectodomain shedding, and inhibiting VE-PTP in lung injury, and will determine the clinical significance of sTie1 as a prognostic biomarker in ARDS.

血管生成素/TIE信号传导调节肺注射中血管泄漏的调节 项目摘要 作为急性肺损伤和急性呼吸窘迫综合征（ARDS）的核心特征，血管泄漏而不是 仅损害气体交换，但还会引发一系列可能带来致命后果的事件。不 目前可以通过稳定肺脉管系统来减少泄漏。这个项目将 确定Angiopietin-2（Ang2），孤儿受体TIE1和VE-PTP的贡献，也称为 血管内皮蛋白 - 酪氨酸磷酸酶，以调节TIE2（TEK）受体信号传导和 肺损伤中血管通透性（“泄漏”）的增加。建立在已知的抗泄漏效应的基础上 Angiopoietin-1（Ang1）和其他TIE2激动剂，该项目将针对最近描述的组成部分 主导血管泄漏严重程度的正反馈回路。触发TIE1的炎性细胞因子 受体外生域的脱落和灭活和内皮细胞中的TIE2信号抑制也 增加FOXO1的转录活性和ANG2的表达，该活性保持TIE2失活和泄漏。 AIM＃1将探索通过通过 逆转肺泡毛细血管内皮细胞中TIE2信号传导的抑制。实验会 确定Ang2过表达，TIE1外生域脱落和灭活以及VE-PTP-的贡献 介导的TIE2去磷酸化，以使TIE2失活和肺损伤中的泄漏。遗传和药理 将使用功能丧失策略来激活TIE2，抑制Ang2，抑制TIE1 ECTODOMAIN 在预防和败血症和反转试验中，脱落并抑制肺脉管系统中的VE-PTP活性 小鼠流感病毒感染。 TIE1，TIE2磷酸化，Ang2，VE-PTP和泄漏将被评估为 读数。泄漏将通过新颖的方法进行局部和测量 在单个肺泡毛细血管的水平上，和20 nm的荧光微球。 AIM＃2将检查 固体TIE1（STIE1）的循环水平升高的功能和预后意义作为生物标志物 肺损伤中的内皮功能障碍。在小鼠中的研究将确定内皮细胞TIE的变化2信号传导 导致STIE1的血液水平升高，以及这些与肺毛细血管泄漏的严重程度有关。 对重症患者的平行研究将探测升高的STIE1水平的临床意义 败血症，有或没有ARDS的发展。这项工作将基于试点研究的数据，显示67％ 23例患者血浆Stie1和Ang2水平升高的重症患者的死亡率，与 STIE1和ANG2正常的人只有8％。共同实验将定义 激活TIE2，抑制ANG2，抑制TIE1外生域脱落，并抑制VE-PTP在肺损伤中， 并将确定STIE1作为ARDS中预后生物标志物的临床意义。