五味子醇对犬慢性心力衰竭JAK2-STAT3信号通路的调控机制

JAK2-STAT3 signaling pathway involved in signaling transmission of almost all cytokines, which play an important role in the processes of chronic heart failure, and have been a hot area of research for recent years. Previous research of our group showed that Schisandrol have the potentially treated efficacy in canine chronic heart failure, but the regulative mechanism of Schisandrol is unclear on JAK2-STAT3 signaling pathway. This research will base on the receptor's substrate of selective specificity, colloidal gold method and IFA are used to analyze the regulative effect of Schisandrol on JAK2-STAT3 signaling pathway. According to the mechanism of cytokines mediated JAK2-STAT3 signaling pathway, RT-PCR, Western Blot, ELISA and FCM are used to analyze the positive/negative regulation of Schisandrol on JAK2-STAT3 signaling pathway. Gene knockout are used to analyze the effect of cardiac function and cardiac protection on Schisandrol mediated JAK2-STAT3 signaling pathway. The mechanism of Schisandrol regulate JAK2-STAT3 signaling pathway will be expounded, and which will provide the scientific basis for the medicinal development of Schisandrol.

JAK2-STAT3信号通路几乎参与了所有细胞因子信号的传递，在慢性心力衰竭的进程中起关键作用，成为近年研究热点。课题组前期研究发现五味子醇对犬类慢性心力衰竭存在潜在的治疗效果，但尚不清楚五味子醇调控JAK2-STAT3信号通路的作用机制。本项目根据JAK2-STAT3信号传导通路受体底物选择的特异性，采用胶体金免疫电镜法和间接免疫荧光法，分析五味子醇对信号通路受体的调控作用；根据细胞因子介导激活JAK2-STAT3信号通路的作用机理，采用荧光定量PCR、Western Blot技术、间接ELISA法和流式细胞技术分析五味子醇激活JAK2-STAT3信号通路正、负向调控作用；结合基因敲除技术，分析五味子醇通过介导JAK-STAT信号通路对心脏功能、心肌保护的作用，阐述五味子醇调控JAK2-STAT3信号通路作用机制,为五味子醇治疗宠物犬心力衰竭机理阐述及其高效利用提供科学依据。

项目重点开展了五味子醇对犬慢性心力衰竭JAK2-STAT3信号通路的调控机制研究。明确了五味子醇对信号通路受体的调控作用；根据细胞因子介导激活JAK2-STAT3信号通路的作用机理，明确了五味子醇激活JAK2-STAT3信号通路正、负向调控作用；结合基因敲除技术，评估了五味子醇通过介导JAK-STAT信号通路对心脏功能、心肌保护的作用，阐述了五味子醇调控JAK2-STAT3信号通路作用机制。通过项目的实施，明确了五味子醇甲在心肌肥大、炎性损伤的保护作用和心脏功能的调节作用；在Jak2-Stat3信号通路的激活、传导异常过程中，五味子醇甲可通过上调表皮生长因子EGF、cTn1(cTnI、cTnT、ET-1)蛋白表达、下调Ang-II、SOCS3、SHP2、PIAS1的表达来维持Jak2-Stat3信号通路激活的动态平衡；Jak2-Stat3信号通路阻断后，推测五味子醇甲也可通过参与其他信号通路来发挥其对心脏的保护作用；通过Jak2-Stat3信号通路阻断后，五味子醇甲对Jak2-Stat3信号通路的激活、传导，阐述了五味子醇对心肌肥大、炎性损伤的保护作用和心脏功能的正向调节机制。