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.

这个R35 MIRA补助金申请解决了理解机制的根本差距， 创伤引起的微血管渗漏，这是全身炎症反应的标志。远景目标 是确定新的目标，可用于改善微血管渗漏的背景下，创伤性损伤， 以改善创伤患者的治疗效果。为了实现这一目标，目前的知识的细胞和 控制微血管渗透性的分子信号必须被显著扩展，包括 促进高渗透性和促进向正常屏障功能消退的那些。而且， 我们知道酒精中毒通常伴随着创伤性损伤， 导致创伤患者的预后较差。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，进入下一个层次的护理，以挽救许多患者， 在创伤后随着时间的推移而恶化，发展为脓毒症和多器官衰竭。为了显著扩大电流 知识库如何微血管通透性高的发展和解决，拟议的研究 利用已变得更广泛可用的新兴方法。这些包括RNA-Seq， 蛋白质组学、代谢组学和脂质组学，提供基因表达变化的无偏分析 和分子景观。将这些方法应用于创伤或细胞/组织的实验模型， 创伤患者将识别与创伤诱导的微血管通透性过高相关的新分子 这将揭示三个关键问题的答案，这些问题必须得到解决，以推进新的治疗方法：1） 酒精中毒和失血性休克激活的哪些内皮信号持续增强 微血管渗漏，终止微血管通透性过高？2)持续的微血管 使用内皮损伤的血浆生物标志物准确预测和监测高通透性，或 白细胞激活，以帮助指导治疗干预？3)如何优化液体复苏， 减少微血管通透性过高，改善血液组织交换，更好地预防器官功能障碍？ 将使用多层次方法来回答这些问题，这些问题以确定的临床相关啮齿动物为特征 酒精中毒合并失血性休克/复苏模型，由培养的内皮细胞支持 细胞模型，这将增加对微血管内皮如何响应的理解的深度， 创伤/休克。该提案还利用了PI在分离完整小静脉进行研究方面的独特专业知识， 为了使平移影响最大化，将利用新的人分离的小静脉渗透性模型。寻找答案 这些关键问题是重要的，因为全面了解激活和 终止微血管通透性过高，涉及的生物标志物，或者血浆中的关键因素是什么 内皮屏障保护，将允许新的，个性化的治疗策略， 延长和改善生命。