Endothelial regulation of inflammation in trauma and hemorrhagic shock

继发于夸大的先天免疫反应的并发症，如多器官衰竭， 是创伤患者晚期死亡的主要原因。我的总体目标是发起一项创新和 翻译研究计划侧重于阐明血管内皮细胞通过 调节宿主对严重创伤的炎症反应。特别是，我的研究集中在 抗凝血酶-硫酸肝素系统的免疫调节功能At引发抗炎 与内皮细胞表面特异性硫酸乙酰肝素蛋白多糖(HSPG)受体结合时的信号转导 含有3-0-硫酸盐(3-0)修饰。我们正在进行的实验表明，ATHSPG的调节失调 系统是一种新的机制，导致严重创伤后的炎症和器官损伤 失血性休克。然而，控制3-0 HSPG表达和AT结合的机制如下 创伤是该领域的一个主要知识缺口。了解这些机制将使我们能够开发出新的 临床工具，以减轻创伤后的异常炎症和治疗或预防随后的器官衰竭。 我提议的未来5年的研究计划将集中在3个发展规划领域，这些领域寻求 阐明1)调节3-0热休克蛋白降解的机制；2)调节3-0热休克蛋白降解的机制 生物合成；3)独特的AT突变体的生物学作用和治疗潜力 炎症时，3-0热休克蛋白的表达减少。这些调查的结果具有广泛的意义 对炎症导致发病的许多情况的影响，如败血症， 移植和新冠肺炎。来自R35奖金的资金将1)使我的高度 以NIGMS使命为指导的创新的长期研究计划；2)推进我们的基础 了解宿主对创伤的炎症反应；以及3)创造新的治疗方法，以改善长期 危重病人的生存和生活质量。

Complications that arise secondary to an exaggerated innate immune response, such as multiple organ failure, are a major cause of late-stage mortality in trauma patients. My overall goal is to initiate an innovative and translational research program focused on elucidating mechanisms through which the vascular endothelium regulates the host inflammatory response to severe trauma. In particular, my research is focused on the immunomodulatory functions of the antithrombin (AT)-heparan sulfate system. AT elicits anti-inflammatory signaling upon binding to specific heparan sulfate proteoglycan (HSPG) receptors on the endothelial surface that contain a 3-0-sulfate (3-0S) modification. Our ongoing experiments demonstrate that dysregulation of the ATHSPG system is a novel mechanism driving inflammation and organ injury following severe trauma and hemorrhagic shock. However, the mechanisms that govern 3-0S HSPG expression and AT binding following trauma is a major knowledge gap in the field. Understanding these mechanisms will enable us to develop novel clinical tools to attenuate aberrant inflammation following trauma and treat or prevent subsequent organ failure. The next 5 years of my proposed research program will focus on 3 developing programmatic areas that seek to elucidate 1) mechanisms that mediate 3-0S HSPG degradation; 2) mechanisms that regulate 3-0S HSPG biosynthesis; and 3) the biological role and therapeutic potential of unique AT variants capable of regulating inflammation when 3-0S HSPG expression is reduced. Results of these investigations have broad-reaching implications for many conditions in which inflammation contributes to the pathogenesis, such as sepsis, transplantation, and COVID-19. Funding from this R35 award will 1) enable the establishment of my highly innovative, long-term research program that is guided by the NIGMS mission; 2) advance our basic understanding of the host inflammatory response to trauma; and 3) create novel therapeutics to improve longterm survival and quality of life for the critically ill.