卒中防治是亟待解决的医学难题，自噬研究为我们提供了新的契机。然而，促进大自噬能否减轻脑缺血损伤尚存争议，促使我们重新审视自噬促进细胞存活的核心机制。分子伴侣介导的自噬（CMA）能靶向降解错误折叠蛋白，从而区别于传统大自噬；将研究目标从大自噬转向CMA成为调控自噬减轻脑缺血损伤的突破口。申请者前期发表于Stroke的论著证实保护自噬的关键成分溶酶体可减轻脑缺血损伤。最新预实验发现CMA及其重要调节因子TFEB与保护溶酶体密切相关，且脑缺血后CMA的关键蛋白LAMP-2A表达下调；自主设计的增强TFEB活性的短肽Tat-S211可促进CMA减少OGD后神经元死亡。提示：脑缺血后CMA途径受损，调节TFEB可促进CMA减轻脑缺血损伤。本课题拟利用短肽，结合免疫电镜和小动物MRI等技术，阐明TFEB调控CMA的分子机制，证实增强TFEB活性的短肽调控CMA可减轻脑缺血损伤，为卒中防治提供新思路。

Stroke becomes an emergency disease that should be concerned. It’s widely accepted that autophagy could ameliorate brain injury after stroke. However, it is still debated whether enhancing macroautophagy could protect brain against ischemic injury or not. Chaperone-mediated autophagy (CMA) degrades the misfolded proteins with KFERQ sequences, which could be distinguished from macroautophagy. Therefore, focusing on CMA is a new avenue to reduce brain ischemic injury. In our previous research, we reduced brain infarct volume significantly through protecting lysosome, which was the key compartment for autophagy. In the latest study, we observed that CMA and its master regulator TFEB were associated with protecting lysosome; and LAMP-2A, a protein that is essential for CMA, was down regulated after brain ischemic injury. More importantly, we synthesized a peptide named Tat-S211, which enhanced CMA and reduced cell death against oxygen and glucose deprivation (OGD). It is therefore suggested that CMA was inhibited after brain ischemic injury, and modulating TFEB could induce neuroprotection against ischemic stroke through CMA pathway. In the current study, we plan to employ immuno-electron microscopy, MRI, etc. to explore the underlying mechanism of TFEB-CMA in the process of ischemic stroke, as well as to optimize the strategy of using Tat-S211, which will help to shed new light on the avenue of stroke treatment.