The Beneficial Effects of Endothelial Progenitor Cells in the Vascular Dysfunction of Sepsis

内皮祖细胞对脓毒症血管功能障碍的有益作用

基本信息

批准号：
8860643
负责人：
Hongkuan Fan
金额：
$ 37.38万
依托单位：
MEDICAL UNIVERSITY OF SOUTH CAROLINA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-04-01 至 2020-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8860643
关键词：
APACHE II Actins Acute Address Affect Age Angiopoietin-1 Apoptosis Attenuated Biological Markers Blood Vessels Bone Marrow Caring Cause of Death Cell Adhesion Cell Adhesion Molecules Cell Proliferation Cell Survival Cell physiology Cells Clinical Complication Cytoskeleton Data Diagnostic Endothelial Cells Foundations Functional disorder Gender Goals Health Homeostasis Homing Human In Vitro Inflammation Mediators Injury Intensive Care Units Intercellular Junctions Interleukin-10 Interleukin-6 Life Ligation Logistic Regressions Lung Matrix Metalloproteinases Measures MicroRNAs Modeling Multiple Organ Failure Mus Organ Organ failure Outcome Pathogenesis Pathway interactions Patients Pattern Permeability Plasma Play Process Puncture procedure Race Research Role Sepsis Septic Shock Severity of illness Signal Pathway Site Stem cells Survivors TNF gene Therapeutic Time Tissues Umbilical Cord Blood Vascular Diseases Vascular Permeabilities analog chemokine design endothelial dysfunction improved inhibitor/antagonist nanoparticle novel novel therapeutics operation precursor cell protective effect public health relevance targeted treatment therapeutic target treatment strategy

项目摘要

DESCRIPTION (provided by applicant): Septic shock with multiple organ failure is the leading cause of death in non-coronary intensive care units and remains a major health problem in the US. Endothelial cell dysfunction is an important hallmark of septic shock and results in increases in vascular permeability that play critical roles in the pathogenesis of multi-organ failure. Thus, improving endothelial function represents an important potential therapeutic target in sepsis. The long-term goal of our research is to identify novel treatment strategies for the endothelial injury of sepsis. The overall objective for this proposal is to identify the mechanisms by which endothelial progenitor cells (EPCs) modulate endothelial dysfunction in sepsis. EPCs are circulating, bone marrow-derived endothelial precursor cells which have been recently associated with sepsis. Specifically, EPCs from humans with sepsis demonstrate alterations in function compared to healthy controls and EPC proliferation is inversely related to organ dysfunction in human sepsis. Our data demonstrate that treatment with exogenous human cord blood derived EPCs improves survival, attenuates pulmonary vascular leak and improves organ injury in the murine cecal ligation and puncture (CLP) model of polymicrobial sepsis. A better understanding of the mechanisms by which EPCs exert their protective effects is crucial to the design of new therapeutic strategies. Endothelial cells (ECs) and EPCs are known to release exosomes and microparticles containing micro RNAs (miRNAs) that regulate endothelial function and barrier integrity. We have shown that treatment with EPCs alters circulating levels of EC relevant miRNAs in murine sepsis, including miR-126. Our findings provide strong evidence that miR-126 may play an important role in maintaining EPC/EC function and barrier integrity in sepsis. We propose two related hypotheses: 1) Endothelial progenitor cells regulate endothelial function and barrier integrity through release of specific miRNAs in sepsis and 2) Altered expression of miRNAs which regulate endothelial barrier integrity are associated with severity of illness and outcomes in human sepsis. Two specific aims address these hypotheses: Aim 1: Determine the mechanisms by which EPCs affect vascular barrier integrity in murine sepsis. Aim 2: Determine the expression patterns of miRNAs known to modulate endothelial function and barrier integrity in human sepsis. The proposed research will lay a critical foundation for the design of novel therapeutic strategies for sepsis.

描述（由申请人提供）：脓毒性休克伴多器官衰竭是非冠状动脉重症监护病房中死亡的主要原因，并且仍然是美国的一个主要健康问题。内皮细胞功能障碍是脓毒性休克的一个重要标志，并导致死亡人数增加。因此，改善内皮功能是脓毒症的一个重要的潜在治疗目标。我们研究的长期目标是寻找新的治疗策略。该提案的总体目标是确定脓毒症的内皮损伤机制。内皮祖细胞 (EPC) 调节脓毒症中的内皮功能障碍 EPC 是循环的、骨髓来源的内皮前体细胞，最近与脓毒症相关。具体而言，与健康对照和 EPC 相比，来自脓毒症患者的 EPC 表现出功能改变。增殖与人类脓毒症中的器官功能障碍呈负相关。我们的数据表明，使用外源性人脐带血来源的 EPC 进行治疗可提高存活率、减少肺血管渗漏并改善患者的生存率。改善多种微生物败血症的小鼠盲肠结扎穿刺 (CLP) 模型中的器官损伤更好地了解 EPC 发挥保护作用的机制对于设计新的治疗策略至关重要。释放含有调节内皮功能和屏障完整性的微 RNA (miRNA) 的外泌体和微粒。我们已经证明，EPC 治疗会改变 EC 相关的循环水平。小鼠脓毒症中的 miRNA，包括 miR-126，我们的研究结果提供了强有力的证据，表明 miR-126 可能在维持脓毒症中 EPC/EC 功能和屏障完整性方面发挥重要作用。我们提出两个相关假设：1) 内皮祖细胞调节内皮功能。脓毒症中通过释放特定 miRNA 来维持屏障完整性；2) 调节内皮屏障完整性的 miRNA 表达改变与人类脓毒症的疾病严重程度和结果相关。具体目标解决了这些假设：目标 1：确定 EPC 影响小鼠脓毒症血管屏障完整性的机制目标 2：确定已知调节人类脓毒症中内皮功能和屏障完整性的 miRNA 的表达模式。设计脓毒症新治疗策略的重要基础。