PGC1-α是调控线粒体功能及再生的关键分子。最近研究表明，肾小管上皮PGC1-α下调是急性肾损伤（AKI）的重要机制。FOXO1是PGC1-α的转录因子，我们发现它在AKI时被抑制是肾小管PGC1-α在下调的原因。那么，阻遏FOXO1/PGC1-α的机制是什么？特定位点的丝/苏氨酸磷酸化是抑制FOXO1活性的关键。我们在AKI条件下观察到：①阻断丝/苏氨酸激酶RIP-3可保护FOXO1/PGC1-α通路被抑制；②CoIP结果表明RIP-3和FOXO1可相互结合。因此我们提出一条新的AKI信号通路：RIP-3磷酸化FOXO1，进而导致PGC1-α下调。课题拟用ChIP、pull down、质谱、基因突变等技术在体外研究；分别在RIP-3敲除和FOXO1过表达小鼠中验证这条信号通路在AKI中的作用；探索不同RIP-3抑制剂对AKI保护作用。这些工作将为治疗AKI提供新的理论依据和靶点。

PGC1-α is the master regulator of mitochondrial function and biogenesis. Recent study has demonstrated that reduced PGC1-α in renal tubular epithelial cell play an important role on acute kidney injury (AKI). FOXO1 is a transcription factor of PGC1-α. We found that the down-regulated PGC1-α was attributed to the inhibited FOXO1 during AKI. However, the mechanism for the inhibition of FOXO1/PGC1-α pathway is unknown. Serine/threonine phosphorylation in specific domains determines the FOXO1 activity. We found that blockade of RIP-3, a serine/threonine protein kinases, could reduce the inhibition of FOXO1/PGC1-α pathway at AKI condition. Further, the CoIP result demonstrated that the FOXO1 interacted with PGC1-α at AKI condition. Therefore, we proposed a novel pathway of AKI that the RIP-3 could inhibit FOXO1 through phosphorylation and further down-regulate PGC1-α. We plan to study using ChIP, pull down, mass spectrum, and point mutant technique in vitro. Then the hypothesis will be confirmed in the AKI models generated by RIP-3 knock out and FOXO1 overexpression mice in vivo. Finally, the therapeutic effect of various RIP-3 inhibitors will be testified on AKI models. These works will provide new ideas and target for therapy of AKI.