HDAC6 regulation of myeloid cell responses in sepsis

项目摘要 脓毒症是由宿主对感染的反应失调引起的危及生命的疾病。败血症 仍然是世界范围内的一个重大健康问题，死亡率很高。骨髓细胞反应，如 内毒素耐受性、表观遗传修饰、代谢衰竭和细胞凋亡是深刻的 感染败血症，导致免疫细胞和祖细胞的系统性功能障碍。的 脓毒症中骨髓细胞应答的调节在很大程度上仍然未知。组蛋白脱乙酰酶 HDAC6调节多种细胞反应。然而，HDAC6对骨髓细胞的调节 脓毒症的反应尚未研究。我们的初步研究表明，HDAC6是一种 髓样细胞中细胞信号传导的关键介质。骨髓特异性HDAC6缺失降低了 败血症小鼠的死亡率。此外，选择性HDAC6抑制可以调节骨髓细胞增殖， 在小鼠脓毒症模型中的反应。在拟议的研究中，我们将测试假设 HDAC6激活介导脓毒症中的骨髓细胞功能障碍，HDAC6抑制可 改善脓毒症骨髓细胞功能和存活率。

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.