The Role of Pericytes in the Vascular Dysfunction of Sepsis

周细胞在脓毒症血管功能障碍中的作用

• 批准号: 9929884
• 负责人: Hongkuan Fan
• 金额: $ 6.94万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-21 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9929884
• 关键词: Address; Adherens Junction; Apoptosis; Basement membrane; Blood Vessels; Blood capillaries; Caring; Cause of Death; Cell physiology; Cells; Coculture Techniques; Complication; Data; Disease; Drug or chemical Tissue Distribution; Endothelial Cells; Endothelium; Exhibits; Extravasation; FLI1 Transcription Factor; FLI1 gene; Failure; Functional disorder; Genes; Goals; Health; Homeostasis; Inflammation Mediators; Injury; Intensive Care Units; Kidney; Knockout Mice; Knowledge; Label; Lead; Life; Liver; Luciferases; Lung; Mediating; Microcirculation; Multiple Organ Failure; Mus; Organ failure; Outcome; Paracrine Communication; Pathogenesis; Pericytes; Permeability; Plasma; Play; Process; Research; Role; Sepsis; Septic Shock; Signal Transduction; System; TNF gene; Therapeutic; Tight Junctions; Transgenic Mice; Vascular Diseases; Vascular Endothelial Growth Factors; Vascular Permeabilities; cadherin 5; cecal ligation puncture; claudin-1 protein; endothelial dysfunction; exosome; experience; improved; in vivo imaging; kidney vascular structure; nanovesicle; novel; novel therapeutic intervention; occludin; preservation; protein expression; targeted treatment; therapeutic target; treatment strategy

PROJECT SUMMARY/ABSTRACT 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 (EC) dysfunction, manifested by increases in vascular permeability, is an important hallmark of septic shock and plays a critical role in the pathogenesis of multi-organ failure. Pericytes maintain endothelial barrier function and represent a potential therapeutic target in sepsis. However, the processes that govern pericyte viability and their role in barrier function in sepsis have not yet been fully elucidated. Pericytes are specialized cells embedded in the capillary basement membrane that wrap around endothelial cells of the microcirculation throughout the body and are thought to be important regulators of microcirculatory homeostasis. However, the role of pericytes in the endothelial dysfunction of sepsis is largely unknown. Our data demonstrated that pericytes are depleted in the mouse lung and kidney microvasculature during cecal ligation and puncture (CLP)-induced sepsis and pericyte depletion results in vascular leakage. The transcription factor friend leukemia virus integration 1 (Fli-1), is critical to pericyte dysfunction and viability in sepsis by mediating pericyte programmed cell death through pyroptosis. MiR-145 inhibits Fli-1 expression and is abundantly expressed in pericytes; however, during sepsis, miR-145 expression decreases with a concomitant increase in Fli-1 expression. This suggests that miR-145 may play an important role in pericyte viability and, therefore, be an important regulator of vascular permeability. A clearer understanding of how the miR-145/Fli-1 axis regulates pericyte viability in sepsis in a critical gap in knowledge that may lead to novel therapeutic approaches for sepsis. Furthermore, understanding the mechanisms by which pericytes support the vascular barrier integrity in sepsis may also have therapeutic implications. One potential mechanism whereby pericytes communicate with endothelial cells is through paracrine signaling via exosomes. Intriguingly, we have demonstrated that pericyte-derived exosomes but not fibroblast-derived exosomes improve survival in mice subjected to CLP-induced sepsis and that pericyte exosomes contain abundant miR-145. The long-term goal of our research is to identify novel treatment strategies to maintain endothelial barrier function in sepsis. The overall objective for this proposal is to identify the determinants of pericyte viability in sepsis and the mechanisms by which pericytes maintain endothelial barrier function. We hypothesize that pericyte viability regulated by the miR-145/Fli-1 axis is a critical determinant of sepsis outcomes through pericyte- mediated stabilization of endothelial permeability. Three specific aims address this hypothesis: Aim 1: Determine the mechanisms by which the miR-145/Fli-1 axis regulates pericyte function and viability in sepsis. Aim 2: Define the mechanisms by which pericytes and pericyte exosomes regulate EC function. Aim 3: Elucidate the therapeutic potential of pericyte-derived exosomes in CLP-induced sepsis.

项目摘要/摘要 多个器官故障的化粪池休克是非冠军重症监护病房死亡的主要原因 在美国仍然是一个主要的健康问题。内皮细胞（EC）功能障碍，表现为增加 血管通透性是败血性休克的重要标志，在发病机理中起着至关重要的作用 多器官故障。周细胞保持内皮屏障功能，并代表潜在的治疗靶点 败血症。但是，控制周细胞生存能力的过程及其在败血症中的障碍功能中的作用尚未 尚未完全阐明。周细胞是嵌入毛细血管基底膜中的专门细胞 在整个体内的微循环的内皮细胞周围包裹，被认为很重要 微循环稳态的调节剂。但是，周细胞在败血症的内皮功能障碍中的作用 在很大程度上未知。我们的数据表明，周细胞在小鼠肺和肾脏中耗尽 盲肠结扎和穿刺（CLP）诱导的败血症和周细胞耗竭期间的微脉管系统导致 血管泄漏。转录因子朋友白血病病毒整合1（FLI-1），对周细胞至关重要 败血症的功能障碍和生存能力通过介导周细胞编程的细胞死亡通过凋亡。 mir-145 抑制FLI-1表达，并在周细胞中大量表达；但是，在败血症期间，miR-145表达 随着FLI-1表达的同时增加而减小。这表明mir-145可能发挥重要作用 在周细胞生存力中的作用，因此是血管通透性的重要调节剂。更清晰 了解miR-145/fli-1轴如何调节败血症的周围生存能力 这可能会导致败血症的新型治疗方法。此外，了解该机制 周细胞支持败血症中的血管屏障完整性也可能具有治疗意义。一个潜力 周细胞与内皮细胞通信的机制是通过外泌体通过旁分泌信号传导。 有趣的是，我们已经证明了周细胞衍生的外泌体，而不是成纤维细胞衍生的外泌体有所改善 受CLP诱导的败血症和周细胞外泌体的小鼠的存活率含有丰富的miR-145。这 我们研究的长期目标是确定新颖的治疗策略以维持内皮屏障功能 败血症。该提案的总体目的是确定败血症和败血症周围生存能力的决定因素 周细胞维持内皮屏障功能的机制。我们假设周围的生存能力 由miR-145/fli-1轴调节是通过周细胞 - 介导的内皮渗透性稳定。三个具体目的解决了这一假设：目标1： 确定miR-145/fli-1轴调节败血症中周细胞功能和生存能力的机制。 AIM 2：定义周细胞和周细胞外泌体调节EC功能的机制。目标3：阐明 周细胞衍生的外泌体在CLP诱导的败血症中的治疗潜力。