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

程序摘要 在各种情况下，如创伤和细菌或病毒感染，肺血管屏障完整性的丧失是一种 急性肺损伤(ALI)及其严重变异型ARDS的特征。ALI的特点是富含蛋白质的水肿和 最终导致呼吸衰竭。靶向治疗仍然是一个迫切的、尚未得到满足的需求。它现在正变得越来越多 显然，肺内皮细胞是一个复杂的单层，几乎是一个器官本身，不仅由肺泡组成 内皮细胞(EC)，也可在肺微血管、动脉和静脉中发现的特定EC群体。 最近，我们使用rna测序显示，肺内皮细胞显示出显著的基因上调。 参与与免疫功能有关的过程，如白细胞黏附、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，不像EC在其他器官，如大脑或心脏。研究这种免疫调节 肺内皮细胞的功能对于了解EC如何控制免疫和宿主防御至关重要 肺的功能，以及其免疫反应的失调或损害如何导致发病机制 阿里的。该计划建立在前20年实体非凡成功的基础上，这一点从我们的 成就。我们已经帮助建立了肺内皮细胞作为一个节点来理解肺的 对感染和损伤的反应和我们的工作使我们更好地理解了治疗内皮细胞的方法 肺部屏障破裂。这一修订的应用程序，重点是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，中央银行 肺内皮细胞在驱动炎性肺损伤中的作用，同时提供了线索，将导致 到新的肺损伤靶向治疗。项目1将测试翻译后修改的假设 内质网以一种意想不到的方式定位于Spinghosine-1-磷酸受体S1PR1 对肺内皮细胞重新编程以激活导致炎症性肺损伤的信号级联反应。项目2 将测试一种新的肺内皮细胞表达泛素E3连接酶CHFR(Checkpoint with 美国鉴定的叉头和环指结构域)调节VE-钙粘附素介导的内皮屏障完整性 和肺部的先天免疫功能。因此，靶向CHFR有望预防炎症性肺损伤。 项目3将测试肺内皮细胞线粒体功能障碍和诱导有丝分裂的假设 调节内皮再生是恢复动态平衡和预防的关键关卡 炎症性损伤。这些项目由创新的科学核心(表观遗传学和 转录学(核心B)、细胞成像(核心C)和生命成像和生理学(核心D) 将有可能严格地解决肺内皮细胞的先天免疫功能及其在 协调恢复动态平衡。我们希望解开肺的先天免疫功能 血管内皮细胞，从而为开发针对ALI和ARDS的新的靶向治疗提供策略。

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.