Mechanisms of vascular dysfunction in acute systemic inflammation

急性全身炎症中血管功能障碍的机制

• 批准号: 10229404
• 负责人: Ryan J Stark
• 金额: $ 43.23万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10229404
• 关键词: Acute; Affect; Animal Model; Animal Testing; Animals; Biochemical; Biological Assay; Blood Vessels; Cells; Chronic; Clinical; Coagulation Process; Coupled; Critical Illness; Data; Diagnosis; Endothelium; Failure; Functional disorder; Genetic; Goals; Healthcare Systems; Homeostasis; Human; Immune response; Infection; Inflammation; Inflammatory; Lasers; Lead; Left; Leukocyte Trafficking; Ligation; Liquid substance; Mediating; Metabolic Pathway; Microfluidic Microchips; Modeling; Modernization; Modification; Molecular; Monitor; Morbidity - disease rate; Nitric Oxide; Outcome; Oxidative Stress; Pathway interactions; Patients; Pattern; Peptides; Perfusion; Plant Roots; Population; Procedures; Proteins; Reactive Oxygen Species; Research; Signal Transduction; Supportive care; System; Systemic Inflammatory Response Syndrome; Techniques; Testing; Therapeutic; Tissues; Vascular Diseases; Vasodilator Agents; cost; cytokine; drug discovery; effective therapy; endothelial dysfunction; genomic signature; improved; interest; mitochondrial dysfunction; mortality; multimodality; novel; pathogen; patient population; programs; protein aminoacid sequence; protein protein interaction; proteomic signature; spatiotemporal; systemic inflammatory response

PROJECT SUMMARY: The systemic inflammatory response syndrome, driven by a host’s response to inflammatory triggers such as foreign pathogens and cytokines, causes significant dysfunction in the vasculature. This dysfunction is due to the loss of homeostatic mechanisms within the endothelium and manifests as intravascular fluid loss, abnormal leukocyte trafficking, disrupted coagulation and altered vascular tone. Despite its overwhelming and obvious negative effect on patients and their outcomes, targeting vascular pathways, such the vasodilator nitric oxide, has not yielded successful results. The failure of such trials, along with the general absence of effective treatments for acute systemic inflammation, has left clinicians with no therapeutic options beyond supportive care. Unfortunately, the root cause of vascular dysfunction in acute systemic inflammation remains completely unknown and with many unanswered questions. What spatiotemporal protein interactions or metabolic pathways contribute to or counterbalance the dysfunction? Does the presence of vasculopathy lead to specific genomic or proteomic signatures, known as endotypes, and how can they be modeled? What unique endothelial targets exist that can be utilized to improve vascular function and restore homeostasis? To answer these questions and any further that will arise, our research program will focus on three integrated themes. Theme one will explore molecular mechanisms that dysregulate endothelial homeostasis during acute inflammation. Mechanisms such as direct protein-protein interactions, mitochondrial dysfunction and reactive oxygen species signaling will be explored using a variety of techniques including genetic modification, glycolytic and oxidative stress capacity and proximity ligation assays. Theme two will focus on modeling endothelial dysfunction utilizing overlapping procedures in both animals and humans to identify consistent patterns. This theme will test animal models of systemic inflammation in combination with acutely ill human patients using non-invasive vascular reactivity techniques, such as laser doppler perfusion monitoring, coupled with genomic and proteomic signatures. In addition, the use of microfluidic devices (i.e. tissue-on-a-chip) will create a bridge between the more adaptable animal models and the non-adaptable human patient populations to test if a synthetic human system will correlate with data derived from mechanism driven animal studies. The third theme will focus on drug discovery. This theme will use the biochemical mechanisms found in the prior themes to help discover endothelial-specific, targeted treatments. Use of cell-penetrating peptides coupled to novel compounds or peptide sequences will allow cell permeation to the target of interest. In addition, testing of therapies used in chronic vascular dysfunction will be examined to determine if similar mechanisms can be tempered in acute systemic vasculopathy. These integrated themes support the overarching goal of this research program, which is to better understand mechanisms that affect acute endothelial-mediated vascular dysfunction with the overall intent of being able to identify and treat patients with acute vasculopathy during systemic inflammation to improve clinical outcomes.

项目摘要： 由宿主对炎症触发因素的反应（例如）驱动的全身性炎症反应综合征 外来病原体和细胞因子在脉管系统中引起明显的功能障碍。这种功能障碍是由于 内皮内稳态机制的丧失，表现为血管内流体损失，异常 白细胞运输，凝血破坏和血管张力改变。尽管有压倒性和明显的 对患者及其结果的负面影响，靶向血管途径，例如血管扩张剂一氧化氮， 尚未取得成功的结果。此类试验的失败，以及一般没有有效的 急性全身性炎症的治疗方法使临床医生没有治疗选择 关心。不幸的是，急性全身感染中血管功能障碍的根本原因完全保持 未知和许多未解决的问题。什么时空蛋白相互作用或代谢途径 为功能障碍做出贡献还是平衡？血管病的存在是否导致特定的基因组或 蛋白质组学特征，称为内型，如何建模？什么独特的内皮目标 存在可以用来改善血管功能并恢复体内平衡的存在吗？回答这些问题和 将会出现的任何进一步，我们的研究计划将重点关注三个集成主题。主题将探索 急性炎症期间内皮骨稳态失调的分子机制。这样的机制 作为直接蛋白质 - 蛋白质相互作用，线粒体功能障碍和活性氧信号传导将是 使用多种技术进行探索，包括遗传修饰，糖酵解和氧化应激能力以及 接近连接分析。主题第二将重点用于建模使用重叠的内皮功能障碍 动物和人类的程序以识别一致的模式。该主题将测试动物模型 全身性炎症与急性病的人类患者结合使用非侵入性血管反应性 技术，例如激光多普勒灌注监测，再加上基因组和蛋白质组学特征。在 此外，使用微流体设备（即芯片组织）将在更适合适应性的地方建立桥梁 动物模型和非适应人类患者人群测试合成人类系统是否相关 从机制驱动动物研究中得出的数据。第三个主题将重点放在药物发现上。这 主题将使用先前主题中发现的生化机制，以帮助发现内皮特异性， 有针对性的治疗。使用与新型化合物或胡椒序列相结合的细胞穿透宠物的使用将 使细胞渗透感兴趣的目标。此外，测试用于慢性血管功能障碍的疗法 将检查以确定是否可以在急性全身性血管病中温度相似的机制。这些 综合主题支持该研究计划的总体目标，这是更好地理解 影响急性内皮介导的血管功能障碍的机制，总体意图 在全身感染期间鉴定和治疗患有急性血管病的患者，以改善临床结果。