基于DJ-1-Grp75-线粒体复合体Ⅰ调控途径探讨DJ-1介导心肌缺血预适应延迟保护的新机制

DJ-1是最近报道的一种在体内广泛分布、高度保守的具有显著抗氧化应激作用的胞内蛋白。在前一基金资助下我们证实，DJ-1作为内源性保护蛋白参与了心肌缺血预适应（IPC）的延迟保护，其机制与Nrf2-ARE抗氧化通路有关。但DJ-1的心肌保护效应难于完全用Nrf2-ARE通路的激活来解释。显然，寻找DJ-1介导心肌IPC延迟保护的其它机制和靶点具有十分重要的理论意义和应用价值。为此，本研究拟在细胞和整体水平，利用一系列分子生物学实验手段，从DJ-1线粒体内膜亚定位及呼吸链复合体Ⅰ酶活性调节的角度，探讨DJ-1介导心肌IPC延迟保护的新机制，寻找其心肌保护作用的新途径和新靶点，并进一步阐明这一重要的内源性细胞保护物质的生理与病理意义，为缺血性心肌损伤的防治提供新思路和新的干预环节。

DJ-1 is a recently identified cellular protein which is ubiquitously expressed in multiple tissues throughout the body and has a significant role in anti-oxidative stress. Our previous work shown that DJ-1 mediates the delayed cardioprotection of ischemic preconditioning (IPC) against ischemia/reperfusion (I/R) injury at least partially through activation of the Nrf2-ARE pathway. However, the DJ-1-mediated cardioprotection is difficult to be fully explained by only activation of Nrf2-ARE pathway. Obviously, it has important theoretical significance and application value to find the other mechanisms and targets of DJ-1-mediated delayed cardioprotection of IPC. Therefore, in the present study, by using a variety of molecular biology methods, we will further explore the novel targets and mechanisms of DJ-1-mediated IPC delayed cardioprotection from the perspective of DJ-1 mitochondrial translocation and modulation of mitochondrial complex I activity at the cellular and whole-animal levels. This study will provide new strategies for prevention and treatment of acute myocardial injury.