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Murine Circulating Endothelial Precursors (CEPs) and Lung Capillary Repair

小鼠循环内皮前体 (CEP) 和肺毛细血管修复

基本信息

批准号：
8235016
负责人：
ROSEMARY CRISTIAN JONES
金额：
$ 43.47万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8235016
关键词：
Acute Acute Lung Injury Address Adult Affect Alveolar Alveolar Cell Angiogenic Factor Biological Models Blood Blood Circulation Blood Vessels Blood capillaries Bone Marrow Breathing CXCR4 gene Cell Therapy Cells Characteristics Data Development Differentiation Antigens Disease Endothelial Cells Endothelium Engraftment Flow Cytometry Goals Grant Growth Factor Hematopoietic Imaging Techniques Infusion procedures Injury Kinetics Label Legal patent Life Lung Mediating Membrane Modeling Molecular Mus Myelogenous Organelles Oxygen Pathway interactions Phenotype Population Process Pulmonary Hypertension Quantum Dots Recruitment Activity Research Research Design Residual state Resolution Respiratory distress Role Series Signal Pathway Signal Transduction Structure Surface Techniques Vascular Endothelial Growth Factors base capillary digital imaging fluorescence imaging improved injured lung vascular injury molecular phenotype new growth novel preclinical study precursor cell programs public health relevance repaired response therapeutic target trafficking treatment strategy

项目摘要

DESCRIPTION (provided by applicant): This grant proposes preclinical studies to improve understanding of the cellular basis of vascular repair in the adult lung by a blood-derived cell population. We have identified a novel population of circulating endothelial precursors (CEPs) and discovered their potential to repair capillary segments in the murine lung by a previously undescribed angiogenic process. Based on preliminary data, the studies supported by this grant will be guided by three principal hypotheses: (i) in lung vascular injury CEPs fuse to endothelial cells, acquire an endothelial-like phenotype, and engraft into existing capillaries to repair their structure and function; (ii) BMDCs mobilized into the circulation and recruited to the injured lung make a major contribution to capillary repair by CEPs; and (iii) VEGF and SDF-11 signaling mediate the mobilization and recruitment of BMDCs to the injured lung and capillary repair by CEPs. State-of-the-art high resolution and fluorescence imaging approaches (using immunogold labels and quantum dots), and other quantitative approaches, i.e., flow cytometry analyses, will be used. The studies proposed will take advantage of genetically modified mice and a well-characterized model of capillary repair by CEPs in the lung injured by breathing high oxygen. Repair in acute lung injury and in the chronically injured lung - in which capillary networks are lost and then restored - will both be studied. Specifically, we aim to characterize the kinetics and phenotype of murine CEPs as they restore pulmonary capillaries (AIM 1); demonstrate in structural and functional studies, that include myelo-suppression and infusion of BMDCs sub-sets, a causal relationship between BMDCs and capillary repair by CEPs (AIM 2); and demonstrate that selective blockade of VEGF/VEGF-R2 and/or of SDF-11/CXCR4 signaling impair the mobilization and recruitment of BMDCs to the injured lung and capillary repair by CEPs (AIM 3). By understanding the role of CEPs in the salvage of existing capillary networks, the proposed studies should promote the development of cell-based treatment strategies for the acutely injured lung as well as the lung with established capillary loss. PUBLIC HEALTH RELEVANCE: In life-threatening diseases such as the Pulmonary Hypertensions, or following acute lung injury leading to the development of a severe form of Acute Respiratory Distress, vascular injury destroys small blood vessels throughout the lung. Studies are designed to improve understanding of a newly identified process of spontaneous repair of these blood vessels by cells circulating in blood. Further understanding of how such circulating cells salvage existing blood vessels, or trigger growth of new ones, will promote the development of cell-based therapies to restore damaged vascular networks in the lung.

描述（由申请人提供）：这项资助提出了临床前研究，以提高对血源性细胞群修复成人肺部血管的细胞基础的理解。我们已经鉴定了一个新的循环内皮前体细胞（CEP）群体，并发现它们通过先前未描述的血管生成过程修复小鼠肺毛细血管段的潜力。根据初步数据，这笔资助支持的研究将遵循三个主要假设：（i）在肺血管损伤中，CEP与内皮细胞融合，获得内皮样表型，并移植到现有的毛细血管中以修复其结构和功能； (ii) BMDC 动员到循环系统中并募集到受伤的肺部，对 CEP 的毛细血管修复做出了重大贡献； (iii) VEGF 和 SDF-11 信号传导通过 CEP 介导 BMDC 动员和募集至受损肺和毛细血管修复。将使用最先进的高分辨率和荧光成像方法（使用免疫金标记和量子点）以及其他定量方法，即流式细胞术分析。拟议的研究将利用转基因小鼠和 CEP 修复因呼吸高氧而受伤的肺部毛细血管的良好特征模型。急性肺损伤和慢性损伤肺（毛细血管网络丢失然后恢复）的修复都将得到研究。具体来说，我们的目标是表征小鼠 CEP 在恢复肺毛细血管时的动力学和表型 (AIM 1)；在结构和功能研究中证明 BMDC 与 CEP 毛细血管修复之间的因果关系，包括骨髓抑制和 BMDC 亚组输注（AIM 2）；并证明选择性阻断 VEGF/VEGF-R2 和/或 SDF-11/CXCR4 信号传导会损害 BMDC 向受损肺的动员和募集以及 CEP 的毛细血管修复 (AIM 3)。通过了解 CEP 在挽救现有毛细血管网络中的作用，拟议的研究应促进针对急性损伤的肺以及毛细血管损失的肺的基于细胞的治疗策略的开发。公众健康相关性：在肺动脉高压等危及生命的疾病中，或在急性肺损伤导致严重急性呼吸窘迫的情况下，血管损伤会破坏整个肺部的小血管。研究旨在加深对新发现的血液循环细胞自发修复这些血管过程的了解。进一步了解这些循环细胞如何挽救现有血管或引发新血管的生长，将促进基于细胞的疗法的发展，以恢复肺部受损的血管网络。