HDAC6 regulation of myeloid cell responses in sepsis

项目摘要 脓毒症是一种由宿主对感染的反应失调引起的危及生命的疾病。脓毒症 仍然是世界范围内的一个主要健康问题，死亡率很高。髓系细胞反应，如 内毒素耐受、表观遗传修饰、代谢衰竭和细胞凋亡 感染败血症，导致免疫细胞和祖细胞的全身性功能障碍。这个 脓毒症中髓系细胞反应的调节在很大程度上仍不清楚。组蛋白脱乙酰酶 HDAC6调节多种细胞反应。然而，HDAC6对髓系细胞的调节 脓毒症的反应尚未被研究。我们的初步研究表明HDAC6是一种 髓系细胞中细胞信号的关键介体。髓系特异性HDAC6缺失可降低 败血症小鼠的死亡率。此外，选择性抑制HDAC6可以调节髓系细胞 脓毒症小鼠模型的反应。在拟议的研究中，我们将检验这一假设 HDAC6激活在脓毒症中介导髓系细胞功能障碍，而抑制HDAC6可能 改善脓毒症患者的髓系细胞功能和存活率。

Project Summary Sepsis is a life-threatening disease caused by dysregulated host responses to infection. Sepsis remains a major health problem worldwide with high mortality. Myeloid cell responses such as endotoxin tolerance, epigenetic modification, metabolic failure, and apoptosis are profoundly affected in sepsis, which leads to systemic dysfunction of immune cells and progenitor cells. The regulation of myeloid cell responses in sepsis remains largely unknown. The histone deacetylase HDAC6 regulates a variety of cellular responses. However, HDAC6 regulation of myeloid cell responses in sepsis has not been investigated. Our preliminary studies indicate that HDAC6 is a key mediator of cell signaling in myeloid cells. Myeloid-specific HDAC6 deletion reduces the mortality in septic mice. Furthermore, selective HDAC6 inhibition can modulate myeloid cell responses in the mouse models of sepsis. In the proposed studies, we will test the hypothesis that HDAC6 activation mediates myeloid cell dysfunction in sepsis, and HDAC6 inhibition could improve myeloid cell function and survival rate in sepsis.