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.

程序摘要 像创伤和细菌或病毒感染的潜水员一样，肺血管屏障完整性的丧失是一种 急性肺损伤（ALI）的标志及其严重的变体弧。 ALI的特征是富含蛋白质的水肿和 最终呼吸衰竭。靶向疗法仍然是紧迫的未满足需求。现在变得越来越 清楚的是，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），但在肺微血管，动脉和静脉中也发现了特定的EC种群。 最近，我们已经使用RNA-Serever表明肺EC表现出显着的基因上调 参与与免疫功能有关的过程，例如白细胞细胞粘合剂，白细胞迁移和 免疫系统的调节。这一发现与肺EC不断暴露于 外部环境与其他器官（例如大脑或心脏）不同。研究这种免疫调节 肺内皮的功能对于理解EC如何控制免疫力和宿主防御至关重要 肺的功能，以及其功能障碍或免疫响应障碍如何导致发病机理 阿里。该计划以前20年实体的非凡成功为基础，这是我们的证据 成就。我们帮助建立了肺部内皮作为了解肺的节点 对感染和伤害的反应以及我们的工作使得更好地理解治疗内皮的方法 肺部障碍分解。这项修订的应用，重点是神秘的先天免疫功能 肺部内皮，建立在协同和合作的基础上。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，同时提供了线索 针对靶向疗法的新肺损伤。项目1将检验以下假设：翻译后修改 内质网 - 裂解链氨氨酸1-磷酸受体S1PR1意外的方式 重新编程肺内皮激活诱发炎症肺损伤的信号传导级联反应。项目2 将检验以下假设：新型肺内皮细胞表达泛素E3连接酶CHFR（检查点 叉 - 头和无指域）由美国确定的ve-钙粘蛋白介导的内皮屏障完整性调节 和肺部的先天免疫学功能。因此，靶向CHFR具有预防炎症性肺损伤的希望。 项目3将测试肺内皮线粒体功能障碍和线粒体诱导的假设 调节内皮再生，并作为恢复体内稳态和防止的关键检查点 炎症伤害。这些项目得到了创新的科学核心（表观遗传学和 转录组学（核心B），细胞成像（核心C）以及浸润成像和生理学（核心D） 将有可能严格解决肺部内皮的先天免疫功能及其在 策划恢复体内平衡。我们希望揭开肺的先天免疫功能 内皮，因此提供了针对Ali和Ards开发新的有针对性疗法的策略。