Microvascular Leakage in Hemorrhagic Shock and Trauma

失血性休克和创伤中的微血管渗漏

• 批准号: 10406620
• 负责人: JEROME W BRESLIN
• 金额: $ 37.38万
• 依托单位: UNIVERSITY OF SOUTH FLORIDA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10406620
• 关键词: Address; Alcoholic Intoxication; Applications Grants; Biological Markers; Blood; Caring; Cell model; Cells; Development; Endothelial Cells; Endothelium; Experimental Models; Extravasation; Functional disorder; Gene Expression; Goals; Hemorrhagic Shock; Human; Injury; Knowledge; Life; Liquid substance; Methods; Microvascular Permeability; Mission; Modeling; Molecular; Monitor; Multiple Organ Failure; Organ; Outcome; Patients; Permeability; Physicians; Plasma; Proteomics; Public Health; Research; Resolution; Resuscitation; Rodent Model; Sepsis; Shock; Signal Transduction; Therapeutic; Therapeutic Intervention; Time; Tissues; Trauma; Trauma patient; Traumatic injury; United States National Institutes of Health; clinically relevant; design; disability; improved; improved outcome; knowledge base; leukocyte activation; lipidomics; metabolomics; novel; novel therapeutics; personalized therapeutic; pre-clinical; prevent; systemic inflammatory response; tissue trauma; transcriptome sequencing; translational impact; venule

This R35 MIRA grant application addresses a fundamental gap in understanding of the mechanisms that underlie trauma-induced microvascular leakage, a hallmark of the systemic inflammatory response. The long-term goal is to identify novel targets that can be used to ameliorate microvascular leakage in the context of traumatic injury, in order to improve outcomes for trauma patients. To achieve this goal, the current knowledge of the cellular and molecular signals that control microvascular permeability must be significantly expanded, including signals that promote hyperpermeability and those that promote resolution toward normal barrier function. Also, very little is known about how alcohol intoxication, which often accompanies traumatic injury, worsens microvascular leakage leading to poorer outcomes for trauma patients. Until these gaps in knowledge are filled, physicians will not be able to shift beyond current therapeutic paradigms to the next level of care required to save many patients that worsen over time after trauma, developing sepsis and multiple organ failure. To significantly expand the current knowledge base of how microvascular hyperpermeability develops and is resolved, the proposed research capitalizes on emerging approaches that have become more widely available. These include RNA-Seq, proteomics, metabolomics, and lipidomics, which provide unbiased analysis of changes in expression of genes and the molecular landscape. Applying these methods to experimental models of trauma or cells/tissues from trauma patients will identify novel molecules associated with trauma-induced microvascular hyperpermeability that will reveal answers to three key questions that must be addressed in order to advance new therapies: 1) Which endothelial signals activated by alcohol intoxication and hemorrhagic shock sustain increased microvascular leakage, and which terminate microvascular hyperpermeability? 2) Can sustained microvascular hyperpermeability be accurately predicted and monitored using plasma biomarkers of endothelial injury or leukocyte activation, to help guide therapeutic interventions? 3) How can fluid resuscitation be optimized to reduce microvascular hyperpermeability, improve blood-tissue exchange, and better prevent organ dysfunction? A multilevel approach will be used to answer these questions featuring an established, clinically relevant rodent model of combined alcohol intoxication and hemorrhagic shock/resuscitation, supported by cultured endothelial cell models that will increase the depth of understanding about how the microvascular endothelium responds to trauma/shock. This proposal also leverages the PI’s unique expertise with isolating intact venules for study, and to maximize translational impact will utilize a novel human isolated venule permeability model. Finding answers to these key questions is important, because having comprehensive knowledge of the signals that activate and terminate microvascular hyperpermeability, the biomarkers involved, or what key factors in plasma are endothelial barrier-protective, will permit logical development of new, personalized therapeutic strategies to extend and improve life.

这项R35 Mira赠款申请解决了对基础机制的理解上的根本差距 创伤导致的微血管渗漏是全身炎症反应的标志。长期目标 确定可用于改善创伤性损伤中微血管渗漏的新靶点， 以改善创伤患者的预后。为了实现这一目标，目前对细胞和 控制微血管通透性的分子信号必须显著扩大，包括 促进高渗透性和那些促进向正常屏障功能分解的疾病。此外，几乎没有 知道酒精中毒是如何加重微血管渗漏的，酒精中毒通常伴随着创伤损伤 导致创伤患者的预后更差。在这些知识空白被填补之前，医生们不会 能够超越目前的治疗模式，进入下一层次的护理，以挽救许多患者 创伤后随着时间的推移而恶化，发展为败血症和多器官衰竭。要显著扩展当前的 关于微血管高通透性如何发展和解决的知识库，建议的研究 充分利用已得到更广泛使用的新兴方法。其中包括RNA-Seq， 蛋白质组学、代谢组学和脂质组学，它们为基因表达的变化提供了无偏见的分析 以及分子图景。将这些方法应用于创伤的实验模型或来自 创伤患者将识别与创伤诱导的微血管高通透性相关的新分子 这将揭示为了推进新疗法必须解决的三个关键问题的答案：1) 酒精中毒和失血性休克激活的血管内皮细胞信号增强 微血管渗漏，是什么终止了微血管的高通透性？2)微血管可以维持 使用内皮损伤或血管内皮细胞损伤的血浆生物标记物准确预测和监测高通透性 激活白细胞，以帮助指导治疗干预？3)液体复苏如何优化以 减少微血管高通透性，改善血液组织交换，更好地预防器官功能障碍？ 多层次的方法将被用来回答这些问题，以一只已建立的、与临床相关的啮齿动物为例。 培养内皮细胞支持的酒精中毒与失血性休克/复苏联合模型 细胞模型将增加对微血管内皮细胞如何响应的理解的深度 创伤/休克。这项建议还利用了PI在分离完整小静脉进行研究方面的独特专业知识，以及 为了最大限度地发挥翻译效果，将利用一种新的人类隔离小静脉通透性模型。寻找答案 对于这些关键问题来说很重要，因为全面了解激活和 终止微血管高通透性，涉及的生物标志物，或血浆中的关键因素是什么 内皮屏障保护，将允许合理开发新的个性化治疗策略 延长和改善生活。