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

项目摘要 脓毒症是一种发病率高、死亡率高、危及生命的疾病。新的治疗策略 是治疗这种毁灭性疾病的迫切需要。失控内皮炎性 通常导致炎症性血管损伤的反应是导致 脓毒症并发多器官功能衰竭。HDAC6是一种组蛋白脱乙酰酶，已被报道可调节 核蛋白和非核蛋白通过脱乙酰基起作用。在这个项目中，我们将 探讨HDAC6对脓毒症时内皮炎性损伤的调节作用。在我们的预赛中 研究表明，HDAC6基因敲除或选择性的HDAC6抑制可防止 肿瘤坏死因子-α诱导内皮细胞间黏附分子-1表达与α-微管蛋白增加有关 乙酰化和STAT1活性降低。此外，在脓毒症的小鼠模型中，HDAC6 抑制抑制脓毒症诱导的肺细胞间黏附分子-1的表达，诱导α-微管蛋白乙酰化，以及 抑制肺组织中STAT1的激活，这与肺减少有关 炎性损伤，提高存活率。在拟议的研究中，我们将进行一系列 评估HDAC6在脓毒症诱导的内皮炎症中的作用的实验 并探讨HDAC6抑制血管内皮细胞的作用机制 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.