BAG1/BAG3比值调控缺血性脑卒中急性期UPS和自噬降解错误折叠蛋白质的机制研究

缺血性脑卒中引起的蛋白质错误折叠及聚集会导致神经元变性及延迟性死亡。泛素蛋白酶体系统（UPS）与自噬是细胞内蛋白质降解的主要途径，既往被认为是两条独立的通路，但越来越多的研究表明它们可以相互影响及互补。申请人前期研究发现错误折叠蛋白质（MP）的产生会随着脑缺血及再灌注时间的延长而增加，如MP未能被及时降解将聚集并导致UPS功能紊乱，机体降解MP的主要途径从UPS向自噬转化，且在此过程中BAG1/BAG3比值明显降低。因此推测在缺血性脑卒中急性期通过上调BAG3或下调BAG1表达以进一步降低BAG1/BAG3比值，促进UPS向自噬转化，减少MP聚集，减轻UPS功能紊乱，从而保护神经元。本项目拟利用BAG3转基因小鼠，采用体内外缺血性脑卒中模型，通过腺病毒载体转基因调控BAG1/BAG3比值，阐明BAG1/BAG3比值对缺血性脑卒中影响的分子机制，为缺血性脑卒中的治疗提供新的靶点及理论依据。

Protein misfolding and aggregation caused by ischemic stroke will lead to neurodegeneration and delayed neuronal death. The ubiquitin-proteasome system (UPS) and autophagy are 2 major protein quality control pathways in eukaryotic cells. They were previously considered to be 2 independent pathways, but now many studies have shown that they can interact and complement the functions of one another. The applicant’s previous research suggested that the production of misfolded proteins (MPs) increased with the prolongation of cerebral ischemia and reperfusion time. If MPs were not degraded in time, it would accumulate and cause UPS dysfunction. The main pathway for the body to degrade MPs switched from UPS to autophagy, and the BAG1/BAG3 ratio decreased significantly during this process. Therefore, it is speculated that by increasing the expression of BAG3 or decreasing the expression of BAG1 in the acute phase of ischemic stroke to further reduce the BAG1/BAG3 ratio will promote the conversion of UPS to autophagy and enhance the degradation of misfolded proteins, then rescues UPS dysfunction, thereby reduce misfolded protein aggregation, and ultimately protect neurons. On this basis, this project intends to utilize BAG3 transgenic mice, and built in vivo and in vitro ischemic stroke models, and then use adenovirus vector transgene to regulate BAG1/BAG3 ratio to observe the effect of BAG1/BAG3 ratio changes after cerebral ischemia, and further explore the molecular mechanism. This project will provide new therapeutic targets for acute ischemic stroke.