缺血再灌注损伤治疗策略的探索：线粒体靶向治疗药物对线粒体形态及功能的调控

Whether alterations in mitochondrial morphology affect the susceptibility of the organ to ischemia/reperfusion injury is unknown. We hypothesized the modulating mitochondrial morphology protects the organ against ischemia/reperfusion injury. The primary goal of this proposed project is to investigate whether modulating of mitochondrial dynamics by mitochondrial-targeted multifunctional therapeutic agents (indole-tempo conjugates) can protect the local and remote organs against ischemia/reperfusion injury. More specifically, we will focus on investigation of mitochondrial alterations in a cell-based model of ischemia/reperfusion (I/R) injury. In addition, we will demonstrate whether the pharmacological manipulation can affect the sensitivity of mitochondrial membrane permeability and cell death in a cell-based ischemia/reperfusion injury model. Furthermore, we will demonstrate whether pharmacological manipulation can affect the mitochondrial dynamics (mitochondrial fission, fusion, movement and mitophagy) in an in vivo ischemia/reperfusion (I/R) injury model. Finally, we will investigate whether pharmacological manipulation can protect local and remote organs in an acute ischemia/reperfusion murine model. Given that pharmacological manipulation of gene controlling mitochondrial fusion and fission can ameliorate disease phenotypes, we expect the efforts to artificially manipulate mitochondrial dynamics will ultimately lead to new therapeutic approaches for the treatment of ischemia/reperfusion injury.

下肢缺血再灌注可引发局部和远隔脏器损伤，近期研究发现其与线粒体分裂融合蛋白（Drp1、Mfn1、Mfn2及Opa1）的调控和功能有着密切联系，在前期研究中我们合成的线粒体靶向多功能试剂(indole-tempo conjugates)已被证实具有抗炎及抗氧化作用。我们期望通过该线粒体靶向多功能试剂来调控线粒体分裂融合蛋白,进而调控线粒体分裂-融合的动态平衡. 通过调节线粒体的形态及功能，来起到细胞及组织的保护作用。我们将着重研究线粒体形态改变对线粒体膜通透敏感性的影响，同时利用缺血再灌注动物实验来验证线粒体靶向多功能试剂对线粒体分裂/融合蛋白表达水平的调控对局部/远隔脏器的保护作用。本课题研究最终目标是希望线粒体靶向多功能试剂(indole-tempo conjugates)能够改变线粒体的形态已达到改善其功能，利用体内和体外研究，证实其对缺血再灌注造成局部及远隔脏器损伤的保护作用。

下肢缺血再灌注可引发局部和远隔脏器损伤。近期研究发现其与线粒体分裂融合蛋白（Drp1、Mfn1、Mfn2 及Opa1）的调控和功能有着密切联系，在前期研究中我们合成的线粒体靶向试剂已被证实具有抗炎及抗氧化作用。我们探索了不同的线粒体靶向试剂对线粒体形态及线粒体膜通透敏感性的影响。同时利用缺血再灌注动物实验来验证线粒体靶向试剂对线粒体分裂/融合蛋白表达水平的调控及对局部/远隔脏器的保护作用。利用体内和体外研究，证实了线粒体靶向试剂对缺血再灌注造成局部及远隔脏器损伤的保护作用。