Pulmonary Vascular Regeneration via Venous Endothelial Progenitors

通过静脉内皮祖细胞进行肺血管再生

基本信息

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
项目类别：
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

项目摘要

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.

项目概要呼吸道病毒感染是发生急性呼吸窘迫的主要危险因素此外，严重的流感损伤可导致肺部修复无效和持续丧失。肺内皮，特别是微血管系统，由于强烈的炎症而受损。病毒感染的反应，但严重后肺内皮再生的机制尽管脉管系统在气体交换中至关重要，但流感损伤尚未完全阐明。该提案旨在回答有关肺血管再生起源的基本问题我们最近研究了血管祖细胞和驱动内皮修复以应对流感损伤的机制。 COUP-TFII 是一种富含增殖内皮细胞的静脉特异性转录因子，静脉内皮细胞越来越被认为是肺再生所必需的。斑马鱼和小鼠各器官内皮再生的群体，表明肺静脉在我自己的初步数据中，我观察到静脉可能同样含有强大的祖细胞。内皮细胞克隆具有高度增殖性，并且可以跨越该提案的目标 1。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该提案的第二个重点。目的是阐明内皮增殖所需的机制和相互作用。静脉标志物的表达，增殖的内皮细胞分泌 C-C 基序趋化因子配体 2 (CCL2)，趋化因子参与介导损伤期间的炎症反应。通过募集单核细胞衍生的炎症促进小鼠炎症血管生成巨噬细胞，表明 CCL2 在组织修复过程中内皮特异性释放的作用，因此，目标 2。将采用内皮细胞中 CCL2 的条件性暂时缺失和氯膦酸盐脂质体介导的耗竭巨噬细胞以研究内皮源性 CCL2 的缺失是否会影响内皮增殖和随后的血管生成修复将解决肺内皮细胞的中心假设。先前存在的静脉内皮中存在的祖细胞群分泌 CCL2 来募集间质单核细胞提供血管生成生态位该项目的完成将验证静脉内皮作为血管生成的利基。肺再生的重要贡献者，也将有助于识别特定的旁分泌/ 免疫途径可以精确调节和保留有益的免疫反应。