HDAC6 regulation of ICAM-1 expression and endothelial inflammatory signaling in sepsis

项目摘要 脓毒症是一种高发病率和高死亡率的危及生命的疾病。新的治疗策略 来治疗这种毁灭性的疾病不受控制的内皮炎性 反应，这往往导致炎症性血管损伤，有助于发病机制， 脓毒症中的多器官衰竭HDAC 6是一种组蛋白脱乙酰酶，据报道， 核蛋白和非核蛋白通过脱乙酰化发挥作用。在这个项目中，我们将 探讨HDAC 6对脓毒症时内皮炎性损伤调节作用。在我们的初步调查中 研究中，我们证明HDAC 6敲低或选择性HDAC 6抑制可防止 TNF-α诱导内皮细胞ICAM-1的表达，这与α-微管蛋白的增加有关 乙酰化和减少的STAT 1活化。此外，在败血症小鼠模型中，HDAC 6 抑制剂阻断脓毒症诱导的肺ICAM-1表达，诱导α-微管蛋白乙酰化， 抑制肺组织中的STAT 1活化，这与肺组织中的 炎性损伤和提高存活率。在拟议的研究中，我们将进行一系列 评估HDAC 6在脓毒症诱导的内皮炎性细胞因子中的作用的实验 反应，并研究HDAC 6抑制对内皮细胞的治疗机制， 脓毒症中的炎症信号。

Project Summary Sepsis is a life-threatening disease with high morbidity and mortality. New therapeutic strategies are urgently needed to treat this devastating disease. Uncontrolled endothelial inflammatory responses, which often leads to inflammatory vascular injury, contribute to the pathogenesis of multiple organ failure in sepsis. HDAC6, a histone deacetylase, has been reported to modulate nuclear and non-nuclear protein function through deacetylation. In this project, we will investigate HDAC6 regulation of endothelial inflammatory injury during sepsis. In our preliminary studies, we demonstrated that HDAC6 knockdown or selective HDAC6 inhibition prevented TNF-α induced endothelial ICAM-1 expression, which was associated with increased α-tubulin acetylation and reduced STAT1 activation. Furthermore, in mouse models of sepsis, HDAC6 inhibition blocked sepsis-induced lung ICAM-1 expression, induced α-tubulin acetylation, and suppressed STAT1 activation in lung tissues, which was associated with reduced lung inflammatory injury and increased survival rate. In the proposed studies, we will conduct a serial of experiments to assess the role of HDAC6 in sepsis-induced endothelial inflammatory responses, and to investigate therapeutic mechanisms of HDAC6 inhibition against endothelial inflammatory signaling in sepsis.