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

• 批准号: 9246548
• 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
• 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/9246548
• 关键词: ANGPT1 gene; APACHE II; Actins; Acute; Address; Affect; Age; Apoptosis; Attenuated; Blood Vessels; Bone Marrow; Caring; Cause of Death; Cell Adhesion; Cell Adhesion Molecules; Cell Proliferation; Cell Survival; Cell physiology; Cells; Clinical; Complication; Cytoskeleton; Data; Endothelial Cells; Failure; 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; Recruitment Activity; 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; diagnostic biomarker; endothelial dysfunction; exosome; improved; inhibitor/antagonist; nanoparticle; novel; novel therapeutic intervention; novel therapeutics; operation; precursor cell; protective effect; public health relevance; targeted treatment; therapeutic target; treatment strategy

 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)：感染性休克合并多器官衰竭是非冠状动脉重症监护病房的主要死亡原因，在美国仍然是一个主要的健康问题。内皮细胞功能障碍是感染性休克的重要标志，导致血管通透性增加，在多器官衰竭的发病机制中起着关键作用。因此，改善内皮功能是脓毒症治疗的一个重要的潜在靶点。我们研究的长期目标是为脓毒症的内皮损伤寻找新的治疗策略。这项提案的总体目标是确定机制 内皮祖细胞(EPC)通过其调节脓毒症时的内皮功能障碍。内皮祖细胞是一种循环中的、骨髓来源的内皮前体细胞，最近发现与脓毒症有关。具体地说，与健康对照组相比，来自脓毒症患者的内皮祖细胞功能发生了变化，并且在人类脓毒症中，内皮祖细胞的增殖与器官功能障碍呈负相关。我们的数据表明，在小鼠盲肠结扎和穿刺术(CLP)的多菌败血症模型中，外源性人脐血来源的EPC可以提高存活率，减少肺血管渗漏，并改善器官损伤。更好地了解内皮祖细胞发挥保护作用的机制对于设计新的治疗策略至关重要。已知内皮细胞(ECs)和内皮祖细胞(EPC)释放外体和含有微RNA(MiRNAs)的微粒，这些微RNA调节内皮功能和屏障完整性。我们已经证明，在小鼠脓毒症中，内皮祖细胞的治疗改变了EC相关miRNAs的循环水平，包括miR-126。我们的发现提供了强有力的证据，表明miR-126可能在维持脓毒症的EPC/EC功能和屏障完整性方面发挥重要作用。我们提出了两个相关的假设：1)内皮祖细胞通过释放特定的miRNAs来调节脓毒症的内皮功能和屏障完整性；2)调节内皮屏障完整性的miRNAs的表达改变与人类脓毒症的病情严重程度和预后有关。两个特定的目标解决了这些假设：目标1：确定内皮祖细胞影响脓毒症小鼠血管屏障完整性的机制。目的2：确定已知的在人类脓毒症中调节内皮功能和屏障完整性的miRNAs的表达模式。拟议的研究将为设计新的脓毒症治疗策略奠定关键基础。