ISGylation regulates lung endothelial inflammation

ISGylation 调节肺内皮炎症

基本信息

批准号：
10180376
负责人：
Yutong Zhao
金额：
$ 58.82万
依托单位：
OHIO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-20 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10180376
关键词：
Acute Lung Injury Adult Respiratory Distress Syndrome Anti-Inflammatory Agents Cell Adhesion Molecules Cell physiology Data Development Disease Endothelial Cells Endothelium Exhibits F-Box Proteins Family member Foundations Functional disorder Genes Genetic Transcription Human IL8 gene ISG15 gene Immune response Inflammation Inflammatory Intercellular adhesion molecule 1 Interferons Interleukin-6 Lead Ligase Lung Mediating Modification Molecular NF-kappa B NF1 gene Nuclear Pathogenesis Pathologic Pathway interactions Phosphoric Monoester Hydrolases Phosphorylation Play Post-Translational Protein Processing Process Property Proteins Regulation Reporting Rest Role Scheme Sepsis Serine Severities Site Stimulus Structure of parenchyma of lung Transcriptional Activation Transgenic Mice Ubiquitin Like Proteins Up-Regulation attenuation chemokine endothelial dysfunction isopeptidase lung injury mouse model neutrophil novel therapeutics overexpression p65 response side effect small molecule small molecule inhibitor transcription factor ubiquitin-protein ligase

项目摘要

Abstract Excessive lung microvascular endothelial inflammation is a pathological hallmark of acute respiratory distress syndrome (ARDS). Upon inflammatory stimuli, lung endothelial cells (ECs) increase chemokine and adhesion molecule expression, such as IL-6, and intercellular adhesion molecule 1, ultimately causing neutrophil accumulation at the site of inflammation, endothelial barrier dysfunction, and lung tissue damage in acute lung injury and sepsis. Nuclear transcriptional factor κB (NF-κB) plays a pivotal role in EC inflammation. Inflammatory stimuli trigger phosphorylation of NF-κB component p65, leading to increase p65 transcriptional activity. We revealed that NF-κBp65 can be ISGylated. The ISGylated p65 is inactive in the resting ECs. We also discovered that SCFFBXL19 E3 ligase catalyzes ISGylation of p65, impedes p65 phosphorylation, and mitigates lung EC inflammation. These observations led us to hypothesize that p65 ISGylation by SCFFBXL19 dampens its phosphorylation, transcriptional activation, and lung EC inflammation; and increases in FBXL19 stability mitigates lung EC inflammation through reducing NF-kB activation. To better understand the new modification of p65, in this proposal, we will determine molecular mechanisms by which SCFFBXL19 catalyzes p65 ISGylation and its role in human lung microvascular EC inflammation. And then, we will determine the molecular mechanisms by which p65 ISGylation impedes its phosphorylation and activation in human lung microvascular ECs. Lastly, we will determine if stabilization of FBXL19 alleviates lung EC inflammation in murine models of acute lung injury and sepsis. This application will be the first to characterize SCFFBXL19-mediated ISGylation of NF-κBp65 and determine its role in the regulation of p65 phosphorylation, transcriptional activation, and lung EC inflammation in acute lung injury and sepsis.

抽象的过度的肺微血管内皮炎症是急性肺损伤的病理标志。呼吸窘迫综合征（ARDS）在炎症刺激下，肺内皮细胞（EC）。增加趋化因子和粘附分子的表达，例如 IL-6 和细胞间粘附分子1，最终导致中性粒细胞在炎症、内皮部位积聚屏障功能障碍以及急性肺损伤和脓毒症中的肺组织损伤。转录因子 κB (NF-κB) 在 EC 炎症刺激中发挥着关键作用。触发 NF-κB 成分 p65 的磷酸化，导致 p65 转录活性增加。我们发现 NF-κBp65 可以被 ISG 化，ISG 化的 p65 在静息 EC 中处于非活性状态。我们还发现 SCFFBXL19 E3 连接酶催化 p65 的 ISGylation，阻碍 p65 这些观察结果引导我们进行战斗。 SCFFBXL19 的 p65 ISGylation 抑制其磷酸化、转录激活和肺功能 EC 炎症；FBXL19 稳定性的增加可通过以下方式减轻肺部 EC 炎症：减少 NF-kB 激活为了更好地理解 p65 的新修饰，在这个提案中，我们将确定 SCFFBXL19 催化 p65 ISGylation 的分子机制及其在然后，我们将确定人肺微血管EC炎症。 p65 ISGylation 阻碍其在人肺中磷酸化和激活的机制最后，我们将确定 FBXL19 的稳定是否会减轻肺 EC。急性肺损伤和脓毒症小鼠模型中的炎症该应用将是第一个。表征 SCFFBXL19 介导的 NF-κBp65 ISGylation 并确定其在调节中的作用急性肺损伤中 p65 磷酸化、转录激活和肺 EC 炎症的影响和败血症。