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

• 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
• 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' 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

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.

项目总结 内皮细胞排列在所有血管的管腔内，在维持屏障功能方面发挥着关键作用。 脉管系统的。屏障功能减弱以及由此导致的血管通透性增加 血浆蛋白和白细胞已被描述为急性呼吸道等病理情况 窘迫综合征和急性肺损伤。由此产生的组织水肿与充气状态的丧失有关。 肺组织和高死亡率和发病率。我们已经发现，聚合酶三角洲相互作用蛋白- 2(Poldip2)是一种具有多个结合伙伴的蛋白，是肺内皮细胞屏障的重要调节因子 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杂合缺失几乎消除内毒素诱导的屏障功能障碍和血管外渗 白细胞进入肺内，显著提高存活率。Poldip2耗尽对渗透率的影响是 在内皮特异缺失Poldip2的小鼠中出现表型。这些动物的表型是 惊人的是，这表明我们已经确定了一个以前没有被认识到的新的主要疾病靶点 与EC屏障功能障碍有关。在这个项目中，我们将探索分子和细胞机制。 负责这一令人印象深刻的保护，以洞察潜在的新疗法。在第一个目标中，我们 将在体内和体外检测内皮Poldip2在屏障功能和炎症中的特定作用， 采用脂多糖致伤模型。AIM 2旨在定义内皮细胞 Poldip2调节屏障功能和炎症，重点是VE-钙粘蛋白信号和它的作用 与血管生成素-2以及Poldip2相互作用的伙伴NOX4相互作用。最后，在目标3中，我们计划 确定Poldip2的功能是如何在分子和细胞水平上调节的。加起来，这三个人 AIMS将使我们对预防富含蛋白质的浮肿的新治疗靶点有新的认识 和肺损伤后的白细胞外渗，并将描绘潜在的分子机制。 我们的工作将提供对调节渗透性和炎症的基本机制的洞察 对其他炎症性疾病具有潜在的广泛适用性。