肾脏缺血再灌注（IRI）导致的急性肾损伤发病率和死亡率都很高，尚缺乏有效的防治手段。RGMb是骨形成蛋白的辅助受体，在其信号通路调节中发挥重要作用。我们之前的研究显示在UUO损伤中，RGMb损害肾小管上皮的完整性并促进肾小管上皮细胞的凋亡，但是这个现象在肾脏IRI中并没有被观察到。因此本项目研究RGMb在肾脏IRI中的作用及机理。首先，利用肾脏上皮细胞特异性敲除RGMb基因小鼠构建肾脏IRI模型，研究RGMb在肾脏IRI中的作用。其次，分析肾脏IRI中细胞程序性坏死的介导物RIP1、RIP3和MLKL的表达活性变化，研究RGMb与肾脏IRI引起的细胞程序性坏死的关系。最后，利用肾脏上皮TKPTS和PTCs细胞，验证RGMb在细胞程序性坏死中的作用，筛选相关的信号通路，阐明RGMb通过调节细胞程序性坏死影响肾脏IRI的作用机理。本项目的完成将为临床治疗肾脏IRI引起的急性肾损伤提供新思路。

Acute kidney injury (AKI) is a common clinical condition that is associated with considerable morbidity and mortality in humans. Renal ischemia reperfusion injury (IRI) is a common cause of AKI. But there is no effective therapy for this devastating clinical condition. RGMb, a member of the repulsive guidance molecule family, has been identified as co-receptor that enhances BMP signaling. Our previous studies showed that RGMb was highly expressed in tubular epithelial cells and involved in the regulation of apoptosis and tubular injury in the kidney after unilateral ureteric obstruction, but these regulations were not observed in renal IRI. Therefore, the role and mechanism of RGMb in renal IRI will be studied in this project. First, in order to investigate the role of RGMb in renal IRI, we have generated renal tubular specific RGMb knockout mice. We will perform renal IRI on these mice and then analyze renal structure and function. Second, in order to study the effect of RGMb on necroptosis which induced by renal IRI, we will examine the expression and activation of RIP1，RIP3 and MLKL, the three key mediators of necroptosis, during IRI in both wild-type mice and RGMb condition knockout mice. Third, we will use renal tubular epithelial cell lines TKPTS and PTCs to study the molecular mechanism by which RGMb regulates necroptosis. Our study will reveal a novel strategy for renal IRI.