Pulmonary Vascular Regeneration via Venous Endothelial Progenitors

通过静脉内皮祖细胞进行肺血管再生

• 批准号: 10532604
• 负责人: Joanna Wong
• 金额: $ 4.68万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532604
• 关键词: 2019-nCoV; Ablation; Acute Respiratory Distress Syndrome; Address; Alveolar; Alveolar Macrophages; Alveolus; Area; Automobile Driving; Blood Vessels; Blood capillaries; Brain; Cell Proliferation; Chemotaxis; Clone Cells; Data; Development; Dichloromethylene Diphosphonate; Edema; Endothelial Cells; Endothelium; Epithelial; Exhibits; Frequencies; Future; Gases; Goals; Height; Human; Immune; Immune response; Impairment; Individual; Inflammatory; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Injury; Intravenous; Label; Lead; Ligands; Liposomes; Liquid substance; Lung; Mediating; Modeling; Molecular; Mus; Myeloid Cells; Organ; Organogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Physiological; Pneumonia; Population; Proliferating; Proliferation Marker; Pulmonary Edema; Pulmonary veins; Regenerative response; Regulation; Reporter; Respiratory Tract Infections; Risk Factors; Role; Signal Transduction; Source; Specific qualifier value; Techniques; Testing; Time; Transplantation; Umbilical vein; Vascular Endothelial Cell; Vascular Endothelium; Vascular regeneration; Vascular remodeling; Veins; Venous; Viral; Viral Respiratory Tract Infection; Virus; Zebrafish; angiogenesis; apoAI regulatory protein-1; beta-Chemokines; cell type; chemokine; chemokine receptor; conditional knockout; endothelial regeneration; endothelial repair; endothelial stem cell; gamma-Chemokines; improved; in vivo; influenza infection; innovation; interstitial; lung injury; lung regeneration; macrophage; monocyte; mortality; paracrine; preservation; prevent; progenitor; pulmonary function; reconstitution; recruit; repaired; response; restoration; single-cell RNA sequencing; stem cells; targeted treatment; tissue regeneration; tissue repair; transcription factor; venule; virus infection mechanism

Project Summary Respiratory viral infections represent a major risk factor for the development of acute respiratory distress syndrome. Moreover, severe influenza injury can result in ineffective repair and persistent loss of pulmonary function. The lung endothelium, especially the microvasculature, is damaged due to the robust inflammatory response from viral infections, but the mechanisms of pulmonary endothelium regeneration after severe influenza injury are not completely elucidated despite the vasculature’s central importance in gas exchange. This proposal aims to answer fundamental questions about pulmonary vascular regeneration regarding the origin of vascular progenitor(s) and the mechanisms driving endothelial repair in response to influenza injury. We recently demonstrated that COUP-TFII, a vein-specifying transcription factor enriched in proliferating endothelial cells, is necessary for lung regeneration. The venous endothelium is increasingly recognized as a vascular progenitor population for endothelial regeneration in various organs in zebrafish and mice, suggesting that pulmonary veins / venules may similarly harbor potent progenitor cells. In my own preliminary data, I observed that venous endothelial cell clones are highly proliferative and can span into the microvasculature. Aim 1 of this proposal will utilize clonal lineage tracing and orthotopic transplantation techniques to determine if the venous endothelium harbors potent progenitor and proliferative potential during lung regeneration. The second focus of this proposal is to elucidate the mechanisms and interactions that are required for endothelial proliferation. Along with expression of venous markers, proliferating endothelial cells secrete C-C Motif Chemokine Ligand 2 (CCL2), a chemokine involved in mediating the inflammatory response during injury. The CCL2-CCR2 signaling axis promotes inflammatory angiogenesis in mice through recruitment of monocyte derived inflammatory macrophages, indicating a role for endothelial-specific release of CCL2 during tissue repair. Therefore, Aim 2 will employ conditional, temporal deletion of CCL2 in endothelial cells and clodronate-liposome mediated depletion of macrophages to investigate if loss of endothelial-derived CCL2 impacts endothelial proliferation and consequent angiogenic repair. This proposal will address the central hypothesis that a pulmonary endothelial progenitor population present in the preexisting venous endothelium secretes CCL2 to recruit interstitial monocytes to provide an angiogenic niche. Completion of this project will validate the venous endothelium as an important contributor to pulmonary regeneration and will also facilitate identification of specific paracrine / immune pathways that could allow for precise regulation and preservation of the beneficial immune response.

项目摘要 呼吸道病毒感染是急性呼吸窘迫发展的主要危险因素 综合征。此外，严重的影响力损伤可能导致肺部的修复和持续丧失无效 功能。肺部内皮，尤其是微脉管系统，由于炎症性强大而受损 病毒感染的反应，但是严重后肺部内皮再生的机制 尽管脉管系统在天然气交换中的核心重要性，但流感损伤并未完全阐明。这 提案旨在回答有关肺血管再生的基本问题 血管祖细胞和驱动内皮修复的机制响应影响力损伤。我们最近 证明了政变 - TFII是一种富含增殖内皮细胞的静脉特异性转录因子，是 肺部再生所必需的。静脉内皮越来越被认为是血管祖细胞 斑马鱼和小鼠各种器官内皮再生的种群，表明肺静脉 /静脉可能同样含有有效的祖细胞。在我自己的初步数据中，我观察到那个静脉 内皮细胞克隆高度增殖，可以跨越微脉管系统。该提议的目标1将 利用克隆谱系跟踪和原位移植技术来确定静脉内皮是否是否 在肺部再生期间，载有强大的祖细胞和增殖潜力。该提议的第二个重点 是为了阐明内皮增殖所需的机制和相互作用。以及 静脉标记物的表达，增殖的内皮细胞秘密C-C基序趋化因子配体2（CCL2），A 趋化因子参与损伤期间炎症反应。 CCL2-CCR2信号轴 通过募集单核细胞刺激性炎症来促进小鼠的炎症性血管生成 巨噬细胞，表明在组织修复过程中CCL2的内皮特异性释放的作用。因此，目标2 将在内皮细胞中采用有条件的，临时删除CCL2和介导的克膦酸酯 - 乳糖体介导 巨噬细胞的耗竭以调查内皮衍生的CCL2是否会影响内皮增殖和 随之而来的血管生成修复。该提议将解决肺部内皮的中心假设 祖先群体中存在的静脉内皮秘密CCL2招募间质 单核细胞提供一个血管生态生态位。该项目的完成将验证静脉园作为一个 肺部再生的重要贡献者，还将促进特定旁分泌 / 可以准确调节和保存有益免疫反应的免疫途径。