MiR-21/Smad7/TGF-β1信号通路介导线粒体损伤参与慢性肾脏病骨骼肌消耗的机制研究

肌少症表现为肌肉消耗、肌力下降，是慢性肾脏病（CKD）极常见的并发症，显著增加CKD死亡风险，临床应予高度重视。线粒体数量是维持骨骼肌质量与功能的重要因素。申请人前期研究发现CKD患者存在骨骼肌线粒体数量减少和功能障碍。MiR-21参与调控线粒体能量代谢，并在生理病理条件下都与肌肉质量呈负相关。申请人预实验发现CKD小鼠血清和骨骼肌miR-21显著上调，miR-21靶基因Smad7下调，TGF-β1信号异常激活。为了深入探索CKD肌消耗的分子机制，本项目拟进行体内外实验，研究miR-21及其靶基因Smad7与TGF-β1信号通路、线粒体数量和功能的关系，观察骨骼肌线粒体数量、线粒体功能及骨骼肌消耗表型的变化，并尝试局部骨骼肌注射锁核苷酸(LNA)-anti-miR-21、增加线粒体生物合成是否具有抑制CKD肌消耗的作用。研究有助于深入理解CKD骨骼肌消耗的机制，为探索新的干预靶点提供证据。

Sarcopenia manifests as muscle wasting and muscle strength dropping. It is an extremely common complication in chronic kidney disease (CKD), which significantly increases risk of death; and it should be paid great attention in clinical practice. The quantity of mitochondria is one of the key factors of maintaining lean muscle mass and muscle function. MiR-21 was found involving in mitochondrial energy metabolism and it was negative correlated with muscle mass in both physiological and pathological scenario. In our pretest study, miR-21 was found significantly up-regulated in CKD mice serum and skeletal muscle tissue while Smad7, the canonical miR-21 target gene, was found down-regulated. Also, the transforming growth factor-β1 (TGF-β1) signaling pathway was aberrantly activated. To further explored the molecular mechanism of CKD associated muscle wasting, in this study, vivo and in vitro experiments will be carried out to study the relationship among miR-21, its target gene Smad7, TGF-β1 signaling pathway and mitochondrial quantity and function. The change of mitochondria quantity, mitochondrial function and muscle wasting phenotype will be observed. Also, local muscle administration of locked nucleic acid-anti-miR-21 and increase mitochondria biogenesis will be tested whether they would have an inhibitory effect on muscle wasting. This program will help with advancing our understanding the mechanism of CKD associated muscle wasting and providing novel evidence on seeking potential interfering strategy.