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: 10430100
• 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/10430100
• 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.

项目概要： 全身炎症反应综合征，由宿主对炎症触发因素的反应驱动，例如 外来病原体和细胞因子会导致脉管系统显着功能障碍，这种功能障碍是由于。 内皮内稳态机制的丧失，表现为血管内液体流失、异常 白细胞运输、凝血功能紊乱和血管张力改变，尽管其影响是巨大且明显的。 对患者及其结果产生负面影响，针对血管通路，例如血管扩张剂一氧化氮， 此类试验并未取得成功的结果，而且普遍缺乏有效性。 急性全身炎症的治疗方法，使防御者除了支持性治疗外别无选择 不幸的是，急性全身炎症中血管功能障碍的根本原因仍然完全存在。 未知且有许多未解答的问题。 血管病变的存在是否会导致特定的基因组或 蛋白质组特征，称为内型，以及如何对它们进行建模？有哪些独特的内皮靶标？ 是否存在可用于改善血管功能和恢复体内平衡的方法？ 任何进一步的出现，我们的研究计划将集中于三个综合主题，其中一个将探讨。 急性炎症期间内皮稳态失调的分子机制。 由于直接的蛋白质-蛋白质相互作用、线粒体功能障碍和活性氧信号传导将 使用多种技术进行探索，包括基因改造、糖酵解和氧化应激能力以及 主题二将重点关注利用重叠模拟内皮功能障碍。 该主题将测试动物和人类的一致模式。 使用非侵入性血管反应与急性疾病患者相结合的全身炎症 技术，例如激光多普勒灌注监测，加上基因组和蛋白质组特征。 此外，微流体装置（即芯片上的组织）的使用将在更具适应性的 动物模型和不适应的人类患者群体，以测试合成的人类系统是否会相关 第三个主题将集中于药物发现。 主题将使用先前主题中发现的生化机制来帮助发现内皮特异性、 使用与新型或复合肽序列偶联的细胞穿透肽将进行靶向治疗。 允许细胞功能障碍渗透到感兴趣的目标此外，测试用于慢性血管的疗法。 将进行检查以确定是否可以在急性系统性血管病变中调节类似的机制。 综合主题支持该研究计划的总体目标，即更好地理解 影响急性内皮介导的血管功能障碍的机制，总体目的是能够 识别和治疗全身炎症期间患有急性血管病变的患者，以改善临床结果。