LETM1介导线粒体释放CTMP在脑缺血损伤中的分子机制研究

生存信号在细胞存活中发挥核心作用。我们及国外学者均证实：脑缺血损伤后Akt激酶的内源性抑制因子CTMP在细胞质中表达增加，生存信号PI3K/Akt通路活性降低，引起缺血性神经损伤。而CTMP储存于线粒体，缺血损伤后大量释放至胞浆是其发挥负性调控作用的前提，但相关调控机制尚待阐明。我们的最新研究显示：脑缺血损伤后，线粒体转运蛋白LETM1与CTMP的结合增加。据此推测：脑缺血损伤后LETM1活性增强，与CTMP结合增加，介导后者从线粒体大量释放至胞浆而抑制生存信号通路活性，并最终导致神经元死亡。本课题拟在前期研究基础上，采用慢病毒转染与干涉、形态和分子生物学技术，明确LETM1在脑缺血损伤中的关键作用，探索CTMP自线粒体释放的分子机制，通过调控LETM1活性，减少CTMP自线粒体释放，以恢复生存信号PI3K/Akt通路活性，挽救濒死神经元，为开发更为有效的缺血性脑损伤防治策略提供新靶点。

Pro-survival signal plays an important role in regulation of cell survival. Our research showed that carboxy-terminal modulator protein (CTMP), an endogenous inhibitor of Akt, is highly expressed after ischemic injury in the cytosol of neurons, which suppressed the activity of PI3K/Akt pathway. CTMP normally resides in mitochondria. Released CTMP of mitochondria and its accumulation in the cytosol are the prerequisites for Akt down-regulation. Our preliminary experiments showed that LETM1, an anti-porter located at inner membrane of mitochondria, was stably expressed in neurons. Cerebral ischemia induced the interaction of LETM1 with CTMP. On the above-mentioned basis, the current study is designed to investigate the role of LETM1 in the CTMP release from mitochondria, and to verify the potential mechanism that inhibition of LETM1 could inhibit CTMP based down-regulation of PI3K/Akt pathway which may finally decrease neuron damage after ischemia injury by using the lentiviral transfection and interference, function, morphology and molecular biology techniques. Our systematic analysis should shed light on a new target for the development of more effective prevention and treatment strategy on the ischemic brain injury.