Role of Poldip2 in endothelial barrier function and inflammation in the lung

Poldip2 在肺内皮屏障功能和炎症中的作用

基本信息

批准号：
10266211
负责人：
Kathy K Griendling
金额：
$ 67.48万
依托单位：
EMORY UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-23 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10266211
关键词：
Actins Activity Cycles Acute Lung Injury Adherens Junction Adult Respiratory Distress Syndrome Affect Alzheimer&apos s Disease Angiopoietin-2 Animal Model Animals Architecture Arteries Atherosclerosis Attenuated Bacterial Toxins Binding Blood Vessels Cell Cycle Regulation Cell Line Cell Nucleus Cell membrane Cells Cerebrum Cessation of life Coronary DNA Repair Databases Diabetes Mellitus Disease Edema Endothelial Cells Endothelium Extracellular Matrix Extravasation Focal Adhesions Functional disorder Gelatinase A Genes Genetic Goals Impairment In Vitro Inflammation Inflammatory Inflammatory Response Injury Integrins Intracranial Neoplasms Ischemic Stroke KDR gene Kidney Leukocytes Lipopolysaccharides Liquid substance Liver Lung Lung Inflammation Lymphatic Matrix Metalloproteinases Metabolic Middle Cerebral Artery Occlusion Mitochondria Modeling Molecular Molecular Probes Morbidity - disease rate Movement Multiple Sclerosis Mus NADPH Oxidase PECAM1 gene Pathologic Pathway interactions Patients Perinatal mortality demographics Permeability Phenocopy Phenotype Phosphorylation Physiological Plasma Proteins Play Polymerase Prevention Production Property Proteins Pulmonary Edema Reactive Oxygen Species Regulation Role Sepsis Signal Transduction Skeletal Muscle Stroke Structure of parenchyma of lung Testing Therapeutic Tight Junctions Tissues Vascular Permeabilities Work blood-brain barrier disruption cadherin 5 cell type cytokine design disability improved in vivo insight lung injury monolayer mortality new therapeutic target novel novel therapeutics recruit response rho therapeutic target vascular bed

项目摘要

PROJECT SUMMARY Endothelial cells line the lumen of all blood vessels and play a critical role in maintaining the barrier function of the vasculature. Diminished barrier function and the consequent increase in vascular permeability to plasma proteins and leukocytes has been described in pathological conditions such as acute respiratory distress syndrome and acute lung injury. The resulting tissue edema is associated with loss of aerated lung tissue and high mortality and morbidity. We have discovered that Polymerase delta interacting protein- 2 (Poldip2), a protein with multiple binding partners, is an important modulator of lung endothelial barrier function. Remarkably, using a lipopolysaccharide (LPS)-induced lung injury model, we observed that heterozygous deletion of Poldip2 nearly abolishes LPS-induced barrier dysfunction and extravasation of leukocytes into the lung, markedly improving survival. The effect of Poldip2 depletion on permeability is phenocopied in mice with endothelial-specific deletion of Poldip2. The phenotype of these animals is striking, suggesting that we have identified a novel and previously unappreciated major target for diseases related to EC barrier dysfunction. In this project, we will probe the molecular and cellular mechanisms responsible for this impressive protection to gain insight into potential new therapies. In the first aim, we will examine the specific role of endothelial Poldip2 in barrier function and inflammation in vivo and in vitro, using the LPS-induced injury model. Aim 2 is designed to define the mechanisms by which endothelial Poldip2 regulates barrier function and inflammation, focusing on the role of VE-cadherin signaling and its interplay with angiopoietin-2, as well as the Poldip2-interacting partner Nox4. Finally, in Aim 3, we plan to determine how Poldip2 function is regulated at the molecular and cellular levels. Together, these three aims will allow us to gain new insight into a novel therapeutic target for prevention of protein-rich edema and leukocyte extravasation following lung injury and will delineate the underlying molecular mechanisms. Our work will provide insight into a fundamental mechanism regulating permeability and inflammation that has potential broad applicability to other inflammatory diseases.

项目概要内皮细胞排列在所有血管的管腔中，在维持屏障功能方面发挥着关键作用脉管系统的。屏障功能减弱，血管通透性随之增加血浆蛋白和白细胞已被描述在病理条件下，例如急性呼吸道疾病遇险综合征和急性肺损伤。由此产生的组织水肿与通气损失有关肺组织损伤，死亡率和发病率高。我们发现聚合酶δ相互作用蛋白- 2 (Poldip2) 是一种具有多个结合伙伴的蛋白质，是肺内皮屏障的重要调节剂功能。值得注意的是，使用脂多糖（LPS）诱导的肺损伤模型，我们观察到 Poldip2 的杂合缺失几乎消除了 LPS 诱导的屏障功能障碍和外渗白细胞进入肺部，显着提高生存率。 Poldip2 缺失对渗透性的影响是在 Poldip2 内皮特异性缺失的小鼠中进行表型复制。这些动物的表型是令人震惊的是，这表明我们已经确定了一个新的、以前未被重视的疾病主要目标与EC屏障功能障碍有关。在这个项目中，我们将探讨分子和细胞机制负责这种令人印象深刻的保护，以深入了解潜在的新疗法。在第一个目标中，我们将检查内皮 Poldip2 在体内和体外屏障功能和炎症中的具体作用，使用 LPS 诱导的损伤模型。目标 2 旨在定义内皮细胞 Poldip2 调节屏障功能和炎症，重点关注 VE-钙粘蛋白信号传导及其作用与 angiopoietin-2 以及 Poldip2 相互作用伙伴 Nox4 相互作用。最后，在目标 3 中，我们计划确定 Poldip2 功能如何在分子和细胞水平上受到调节。这三个人在一起目标将使我们对预防富含蛋白质的水肿的新治疗靶点获得新的认识和肺损伤后白细胞外渗，并将描述潜在的分子机制。我们的工作将深入了解调节渗透性和炎症的基本机制对其他炎症性疾病具有潜在的广泛适用性。