缺血后适应是指在缺血后再灌注期再次施以一个或多个相对短暂的缺血处理。研究发现，缺血后适应显著改善缺血后的神经功能，但其分子机制尚未阐明。申请人前期研究提示，线粒体功能蛋白VDACs介导缺血后适应的线粒体保护作用。本项目拟采用生物化学、分子生物学、药理学和组织学等方法，从整体和细胞水平证实本项目的设想：缺血后适应一方面可以稳定VDACs的表达，维持细胞内钙稳态；另一方面激活PI3K/Akt信号通路，抑制GSK-3beta的活性，稳定VDAC1-HK1信号复合体，从而发挥抗凋亡作用。本项目还将探明缺血后适应在转录和转录后水平调控VDACs稳定表达的分子机制，旨在发现神经保护作用的关键信号分子，为缺血性脑卒中神经保护药物的研发提供潜在的靶点。

Ischemic postconditioning, which refers to a single or a series of brief interference in the cerebral blood supply performed after a prolonged severe form of ischemic insult, has been reported to continuously improve neuronal functions after stroke. However, the molecular mechanisms responsible for such intraneous neuroprotection largely remain unknown. Previously, we found that a mitochondrial functional protein family of VDACs contributes to mitochondrial protection induced by ischemic postconditioning. Here, we propose that the ischemic postconditioning stables the expression of VDACs and then maintains the calcium homeostasis; on the other side, the ischemic postconditioning activates PI3K/Akt signaling, inhibits the activity of GSK-3beta and the subsequent disassembly of VDAC1-HK1 complex, which leads to anti-apoptotic effects. We will demonstrate such hypothesis in cultured neurons and ischemic animal models using the methods of biochemistry, molecular biology, pharmacology, and histology, etc. We will also investigate the transcriptional and post-transcriptional regulation mechanisms of VDACs following ischemic postconditioning. This study will reveals key signal molecules responsible for the neuroprotection and provides potential targets for the treatment of brain ischemia.