Endothelial regulation of inflammation in trauma and hemorrhagic shock

继发于过度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个创新的， 翻译研究计划的重点是阐明机制，通过血管内皮细胞 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（AT）-硫酸乙酰肝素系统的免疫调节功能。抗过敏抗炎 在与内皮表面上的特异性硫酸乙酰肝素蛋白聚糖（HSPG）受体结合后的信号传导， 含有3 - 0-硫酸酯（3 - 0S）修饰。我们正在进行的实验表明，ATHSPG的失调 系统是严重创伤后驱动炎症和器官损伤的新机制， 失血性休克然而，控制3 - 0S HSPG表达和AT结合的机制， 创伤是该领域的一个主要知识空白。了解这些机制将使我们能够开发新的 减轻创伤后异常炎症并治疗或预防随后的器官衰竭的临床工具。 未来5年，我提出的研究计划将集中在3个发展纲领领域，寻求 阐明1）介导3 - 0S HSPG降解的机制; 2）调节3 - 0S HSPG的机制 生物合成;和3）能够调节生物合成的独特AT变体的生物学作用和治疗潜力。 当3 - 0S HSPG表达减少时，炎症。这些调查的结果具有广泛的意义， 对于许多炎症导致发病的疾病，例如脓毒症， 移植和新冠肺炎从这个R35奖的资金将1）使我的高度建立 创新的，长期的研究计划，这是由NIGMS使命的指导; 2）推进我们的基本 了解宿主对创伤的炎症反应; 3）创造新的治疗方法，以改善长期的 提高危重病人的生存率和生活质量

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.