HDAC6通过调控PHB1蛋白转录后修饰影响脓毒症氧化应激反应的机制研究

Sepsis is a syndrome with multiple organ or tissue damage caused by systematic inflammatory reactions resulting from infection and trauma. The major causes of tissue damage are the inflammation and oxidation during sepsis. Previous studies have been focused on the inflammatory responses, but few on the effect of excessive oxidation. HDAC6 is a histone deacetylase. Previous studies have been reported that the expression of HDAC6 was dramatically increased in the patients with sepsis. Meanwhile, our research group has firstly found that the expression of PHB1 was decreased in sepsis patients, and is accompanied by the dyfunction of mitochondria. According to our previous studies, we hypothesized that HDAC6 may regulate the level of PHB1 in cells through regulating the protein modification after transcription and affect the stability of mitochondria and the level of oxidant, promote the tissue damage caused by excessively oxidative responses. To demonstrate this hypothesis, we constructe the sepsis mouse model, lentivirus-mediated gene overexpression and knockdown to investigate the detailed mechanisms of the regulation of HDAC6 on the function of mitochondria. This project provide new targets for the therapy of sepsis in clinical.

脓毒症是一种全身炎症反应综合征，炎症和过氧化是脓毒症造成器官损伤的主要原因。HDAC6是一种组蛋白去乙酰化酶。我们研究发现在脓毒症患者体内HDAC6与PHB1的表达负相关并伴随线粒体功能失调和紊乱，推测在脓毒症中HDAC6可能通过调控PHB1介导的线粒体功能来影响脓毒症的发病过程。为证实这一假说，我们使用脓毒症动物模型、荧光素酶、免疫共沉淀等技术，进行了以下三方面的工作：在临床和动物水平上验证HDAC6与PHB1及线粒体功能的相关性；同时在细胞和分子水平上探讨HDAC6调控PHB1并影响线粒体功能的分子机制；并在临床和疾病水平上验证HDAC6作为脓毒症治疗药物靶点的可行性及效果。通过以上研究，明确HDAC6通过调控细胞内PHB1的水平、进而影响线粒体相关功能的稳定性、从而促进脓毒症发生的分子机制，对揭示脓毒症过程中氧化损伤机制具有重要意义，将从新的视角为临床脓毒症的防治提供新的药物靶点。

脓毒症是一种全身炎症反应综合征，炎症和过氧化是脓毒症造成器官损伤的主要原因。目前研究显示如果能够有效地控制和减弱脓毒症造成的线粒体损伤，就能够有效地降低脓毒症对机体组织器官所造成的损伤。HDAC6是一种组蛋白去乙酰化酶。我们前期研究发现在脓毒症患者体内HDAC6与PHB1的表达负相关并伴随线粒体功能失调和紊乱。在本项目的支持下，本课题组通过临床样本、脓毒症大鼠模型及细胞模型证明了：1）在脓毒症发生过程中，组蛋白乙酰化酶HDAC6与线粒体膜蛋白PHB1存在相互作用并与炎症引起的巨噬细胞线粒体功能障碍存在相关性；2）在脓毒症大鼠模型中，HDAC6可通过PHB1调控线粒体功能障碍；3）证实了HADC6和PHB1存在上下游关系。为开发靶向巨噬细胞线粒体功能紊乱的药物提供了理论依据。