HDAC3调控炎症小体在缺血性脑损伤中的意义及其机制研究

炎症反应参与缺血性脑损伤的整个病理过程，是影响脑卒中预后的主要因素之一。炎症小体是炎症产生的起始环节。它是一种多蛋白复合体，调控caspase-1所介导的1L-1β和IL-18的产生和成熟。HDAC3是组蛋白去乙酰化酶（Histone deacetylases, HDACs）的一个亚型，能够调控炎症小体的成分蛋白的表达，同时慢病毒包装的HDAC3干扰质粒能降低卒中小鼠的梗死面积。我们将采用慢病毒包装的HDAC3干扰质粒, 选择性HDAC3抑制剂RGFP966以及HDAC3基因敲除小鼠，系统地在体内外脑缺血模型上，以及临床角度：1) 明确炎症小体在缺血性脑损伤发生和发展中的病理意义；2) 证明抑制HDAC3调节卒中后炎症小体保护缺血性脑损伤；3）探讨HDAC3调节炎症小体的相关分子机制是否与p65的乙酰化有关，并进一步使用蛋白组学的方法寻找更多的作用靶点，为临床治疗的新思路提供依据。

Inflammation is a critical pathological mechanism in the development of ischemic brain injury. Inflammasome is the initiation of inflammation. It is a 700KD protein complex, which locates in the cytoplasma and senses exogenous or endogenous stimulation. Inflammasome recruits caspase-1 and facilitates the maturation and secretion of 1L-1β and IL-18. HDAC3 (Histone deacetylase 3) belongs to the HDAC family, participates in multiple signaling transductions through down-regulating the acetylation of histone proteins and non-histone proteins. Our study demonstrated that HDAC3 inhibitor decreased the expression of inflammasome. Additionally, lenti-virus wrapped HDAC3 shRNA decreased the infarcted size of ischemic stroke animal model. In the program, with the application of lenti-virus wrapped HDAC3 shRNA, HDAC3 knock-out mice and selective HDAC3 inhibitor, we are going to elucidate the following questions: 1) whether inflammasome plays a role in the pathogenesis of stoke patients and experimental stroke animals. 2) whether HDAC3 inhibition could modulate inflammasome and protect against ischemic brain injury. 3) whether modulation of inflammasome by HDAC3 is related to the acetylation of p65. Solving these questions may help us to find out new strategies to treat ischemic stroke in the clinic.