The Lung Endothelium as an Instructive Niche for the Innate Immune System during Vascular Injury

肺内皮细胞作为血管损伤期间先天免疫系统的指导性生态位

• 批准号: 10706498
• 负责人: DOLLY MEHTA
• 金额: $ 233.93万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-20 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10706498
• 关键词: AKT1 gene; Acute Lung Injury; Acute Respiratory Distress Syndrome; Address; Adherens Junction; Alveolar; Angiopoietin-2; Area; Arteries; Automobile Driving; Bacterial Infections; Biogenesis; Blood; Blood Vessels; Brain; COVID-19 pandemic; Calcium Signaling; Cause of Death; Cell Adhesion; Cell membrane; Cells; Collaborations; Complex; Cues; Data; Defense Mechanisms; Development; Disease; Disease Progression; Edema; Endoplasmic Reticulum; Endothelial Cells; Endothelium; Environment; Epigenetic Process; Exposure to; FOXO1A gene; Foundations; Gene Expression Regulation; Generations; Genetic Transcription; Goals; Health; Heart; Homeostasis; Host Defense; Human; Image; Immune; Immune response; Immune system; Immunity; Immunoglobulin binding proteins; Impairment; Infection; Inflammation; Inflammatory; Injury; Innate Immune Response; Innate Immune System; Leadership; Leukocytes; Ligation; Liquid substance; Lung; Mediating; Membrane; Metabolism; Mitochondria; Mus; Natural regeneration; Organ; Organelles; PINK1 gene; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Phosphotransferases; Physiology; Population; Process; Proteins; Pulmonary Inflammation; Regulation; Resolution; Respiratory Failure; Ring Finger Domain; Role; Signal Pathway; Signal Transduction; Supportive care; Surface; Tennis; Testing; Time; Trauma; Ubiquitination; Up-Regulation; Variant; Vascular Endothelial Cell; Veins; Ventilator; Virus Diseases; Work; alveolar epithelium; cadherin 5; cellular imaging; checkpoint modulation; court; effective therapy; endothelial regeneration; formyl peptide; immune activation; immune function; immunoregulation; inflammatory lung disease; innate immune function; innovation; inorganic phosphate; intravital imaging; lung imaging; lung injury; lung repair; migration; mitochondrial dysfunction; monolayer; mortality; neutrophil; new therapeutic target; novel; prevent; programs; pulmonary function; receptor; response; restoration; spatiotemporal; success; synergism; targeted treatment; trafficking; transcriptome sequencing; transcriptomics; two-photon; ubiquitin-protein ligase; ultra high resolution; vascular injury

ABSTRACT OF PROGRAM The loss of lung vascular barrier integrity in settings as diverse as trauma and bacterial or viral infections is a hallmark of acute lung injury (ALI) and its serious variant ARDS. ALI is characterized by protein-rich edema and ultimately respiratory failure. Targeted therapies remain an urgent unmet need. It is now becoming increasingly clear that the lung endothelium is a complex monolayer, almost an organ itself, consisting of not only alveolar endothelial cells (EC) but also specific EC populations found in pulmonary microvessels, arteries and veins. Recently, we have shown using RNA-sequencing that the lung EC demonstrate significant upregulation of genes involved in processes related to immune function such as leukocyte cell adhesion, leukocyte migration, and regulation of immune system. This finding was consistent with lung EC being continuously exposed to the external environment, unlike EC in other organs such as the brain or heart. Studying this immune regulatory function of the lung endothelium is crucial for understanding how the EC controls immunity and the host defense function of lungs, and also how its dysregulation or impairment of the immune response leads to pathogenesis of ALI. This Program builds on the extraordinary success of a previous 20-year entity, evident by our accomplishments. We have helped establish the lung endothelium as a node for understanding the lung’s response to infection and injury and our work has led to better understanding of ways of treating endothelial barrier breakdown in lungs. This revised application, focusing on the enigmatic innate immune function of the lung endothelium, is built on foundations of synergy and collaborations. Our Supporting data show the central role of the lung endothelium in driving inflammatory lung injury, and at the same time provides clues that will lead to new lung injury targeting therapies. Project 1 will test the hypothesis that the post-translationally modified endoplasmic reticulum-localized spinghosine-1-phosphate receptor S1PR1 in an unexpected manner reprograms lung endothelium to activate a signaling cascade that induces inflammatory lung injury. Project 2 will test the hypothesis that a novel lung endothelial cell expressed ubiquitin E3 ligase CHFR (checkpoint with fork-head and ring finger domain) identified by us regulates VE-cadherin-mediated endothelial barrier integrity and lung’s innate immune function. Targeting CHFR thus holds promise for preventing inflammatory lung injury. Project 3 will test the hypothesis that lung endothelial mitochondrial dysfunction and induction of mitophagy regulate endothelial regeneration and serve as a key check point for restoring homeostasis and preventing inflammatory injury. These Projects are supported by innovative scientific Cores (Epigenetics and Transcriptomics (Core B), Cellular Imaging (Core C), and Intravital Imaging and Physiology (Core D) that will make it possible to rigorously address the innate immune function of the lung endothelium and its role in orchestrating restoration of homeostasis. We hope to unravel the innate immune function of the lung endothelium, thus providing strategies to develop new targeted therapies against ALI and ARDS.

项目摘要 在创伤和细菌或病毒感染等多种情况下，肺血管屏障完整性的丧失是一个重要原因 急性肺损伤 (ALI) 及其严重变异型 ARDS 的标志。 ALI 的特点是富含蛋白质的水肿 最终呼吸衰竭。靶向治疗仍然是一个迫切的未满足的需求。现在已经越来越 明确肺内皮是一个复杂的单层，几乎是一个器官本身，不仅由肺泡组成 内皮细胞 (EC) 以及肺微血管、动脉和静脉中发现的特定 EC 群体。 最近，我们使用 RNA 测序表明，肺 EC 的基因显着上调 参与与免疫功能相关的过程，例如白细胞粘附、白细胞迁移和 免疫系统的调节。这一发现与肺 EC 持续暴露于 外部环境，与其他器官（如大脑或心脏）中的 EC 不同。研究这种免疫调节 肺内皮的功能对于理解 EC 如何控制免疫和宿主防御至关重要 肺功能，以及其失调或免疫反应受损如何导致发病机制 阿里的。该计划建立在前 20 年实体取得的非凡成功的基础上，这一点从我们的 成就。我们帮助建立了肺内皮作为了解肺的节点 对感染和损伤的反应以及我们的工作使人们更好地了解了治疗内皮细胞的方法 肺部屏障崩溃。这个修订后的应用程序，重点关注神秘的先天免疫功能 肺内皮细胞是建立在协同和协作的基础上的。我们的支持数据显示了中央 肺内皮在驱动炎症性肺损伤中的作用，同时提供了导致炎症性肺损伤的线索 新的肺损伤靶向疗法。项目 1 将检验翻译后修饰的假设 以意想不到的方式定位于内质网的 1-磷酸鞘氨醇受体 S1PR1 重新编程肺内皮以激活信号级联，诱导炎症性肺损伤。项目2 将检验以下假设：一种新型肺内皮细胞表达泛素 E3 连接酶 CHFR（检查点为 我们鉴定的叉头和无名指结构域可调节 VE-钙粘蛋白介导的内皮屏障完整性 和肺的先天免疫功能。因此，针对 CHFR 有望预防炎症性肺损伤。 项目 3 将检验肺内皮线粒体功能障碍和线粒体自噬诱导的假设 调节内皮再生并作为恢复体内平衡和预防的关键检查点 炎症损伤。这些项目得到创新科学核心（表观遗传学和 转录组学（核心 B）、细胞成像（核心 C）以及活体成像和生理学（核心 D） 将有可能严格解决肺内皮的先天免疫功能及其在 协调体内平衡的恢复。我们希望解开肺部的先天免疫功能 内皮细胞，从而为开发针对 ALI 和 ARDS 的新靶向疗法提供策略。