自噬经由p62/SQSTM1蛋白途径在脑梗死后出血转化中作用机制的实验研究

Hemorrhagic transformation (HT) is an important complication after ischemic stroke, and the mechanisms of brain injury/protection after HT is still mysterious. Our previous research indicated that iron toxicity contributed to both HT development and autophagy activation. The sequestosome 1/p62 as a functional link between autophagy and misfolded polyubiquitinated protein (UP). It is stress-responsive and plays an important role in the proteasomal and /or autophagic clearance of misfolded and aggregation-prone proteins after intracerebral hemorrhage. This project focuses on the following issues in both vivo and vitro studies: 1) to investigate autophagy activation in the brain tissue around injury after HT; and to confirm the role of autophagy around injury after HT; 2) to explore the inner mechanism underlying autophagy after HT: the role of p62/SQSTM1 as a functional link in the autophagic cleanrance of UP after HT. In conclusion, this project plans to investigate the relation between HT injury and autophagy, which is helpful to improve our understanding in the mechanisms of brain injury and find the new therapies after HT.

脑梗死后出血转化（HT）是缺血性卒中严重的并发症之一。对HT后神经损伤和保护机制的研究是本课题探索的重点。本课题组前期成功构建了HT大鼠模型，并证实铁离子在HT的发生中扮演重要角色，而铁离子同样可以激活自噬。p62/SQSTM1蛋白介导多聚泛素化蛋白（UP）经由自噬-溶酶体途径降解可能是脑出血后自噬发挥作用的机制。本研究拟在原有工作基础上，利用成熟的大鼠HT模型和原代培养神经元，利用多种免疫及分子生物学技术研究以下问题：1）HT后在损伤脑组织灶周是否存在自噬的激活；自噬的激活在HT中起到的作用是保护还是损伤；2）在HT中自噬的通路，其发挥作用是否通过p62/SQSTM1介导UP经由自噬-溶酶体途径清除。该课题有助于深入了解HT后脑损伤与脑保护的机制，为我们寻找HT新的靶点和治疗方案提供线索。

脑梗死后出血转化（HT）是缺血性卒中严重的并发症之一。对出血转化后神经损伤和保护机制的研究以及对HT的有效预测是本课题探索的重点。本课题组通过临床梗死后出血血清样本的收集，成功构建的HT大鼠模型，以及原代培养神经元，利用多种免疫及分子生物学技术证实了：1) 出血转化发生后在损伤脑组织灶周存在自噬的激活；2) 自噬的激活在出血转化中起到的是保护作用；3）在出血转化中自噬的通路发挥作用与p62/SQSTM1介导UP途径相关；4）梗死后出血转化的预测因子包括Axl，DKK3，和VEGF，脑血流自动调节功能受损可能是出血损伤的潜在机制，为进一步寻找HT新的预测因子、研究靶点和治疗方案提供线索。