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: 10753505
• 负责人: Joanna Wong
• 金额: $ 4.77万
• 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/10753505
• 关键词: 2019-nCoV; Ablation; Acute Respiratory Distress Syndrome; Alveolar; Alveolar Macrophages; Alveolus; Area; Automobile Driving; Blood Vessels; Blood capillaries; Brain; Cell Proliferation; Cell Separation; Cell secretion; Chemotaxis; Clone Cells; Data; Development; Dichloromethylene Diphosphonate; Edema; Endothelial Cells; Endothelium; Epithelium; Exhibits; Frequencies; Future; Gases; Goals; Height; Human; Immune; Immune response; Impairment; Individual; Infiltration; Inflammatory; Inflammatory Response; Influenza; Influenza A Virus, H1N1 Subtype; Injury; Intravenous; Label; Ligands; Liposomes; Liquid substance; Lung; Macrophage; Mediating; Modeling; Molecular; Mus; Myeloid Cells; Organ; Organogenesis; Pathway interactions; Patient-Focused Outcomes; Patients; Physiological; Pneumonia; Population; Proliferating; 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; Virus Diseases; 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; 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

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 呼吸道病毒感染是导致急性呼吸窘迫的主要危险因素 综合征此外，严重的流感损伤可导致无效的修复和肺功能的持续丧失。 功能肺内皮，特别是微血管，由于强烈的炎症反应而受损。 病毒感染的反应，但肺内皮再生的机制，严重 尽管脉管系统在气体交换中具有中心重要性，但流感损伤尚未完全阐明。这 该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对流感损伤的反应。我们最近 证明COUP-TFII，一种在增殖内皮细胞中富集的静脉特异性转录因子， 肺再生所必需的。静脉内皮细胞作为血管祖细胞的作用日益受到重视 在斑马鱼和小鼠的各种器官中，内皮再生的群体，表明肺静脉 /小静脉可以类似地容纳有效的祖细胞。在我自己的初步数据中，我观察到静脉 内皮细胞克隆是高度增殖的，并且可以跨越进入微脉管系统。本提案的目标1将 利用克隆谱系追踪和原位移植技术来确定静脉内皮是否 在肺再生过程中具有强大的祖细胞和增殖潜力。本次提案的第二个重点 是阐明内皮细胞增殖所需的机制和相互作用。沿着 静脉标记物的表达，增殖的内皮细胞分泌C-C基序趋化因子配体2（CCL 2）， 趋化因子参与介导损伤期间的炎症反应。CCL 2-CCR 2信号轴 通过募集单核细胞衍生的炎性血管生成促进小鼠中的炎性血管生成 巨噬细胞，表明在组织修复过程中CCL 2的内皮特异性释放的作用。目标2 将采用内皮细胞中CCL 2的条件性暂时缺失和氯膦酸盐-脂质体介导的 消耗巨噬细胞以研究内皮源性CCL 2的丧失是否影响内皮增殖， 随后的血管生成修复。这项建议将解决中心假设，肺内皮细胞 存在于预先存在的静脉内皮中的祖细胞群分泌CCL 2以募集间质 单核细胞以提供血管生成小生境。该项目的完成将验证静脉内皮作为 肺再生的重要贡献者，也将有助于识别特定的旁分泌/ 免疫途径，可以允许精确调节和保护有益的免疫反应。