LncRNA-IMP靶向FUNDC1调控线粒体自噬在糖尿病肾病足细胞损伤中的作用与机制研究

足细胞损伤是糖尿病肾病（DN）发病核心环节，阻断足细胞损伤可有效抑制DN的发生发展，但足细胞损伤机制尚不明确。前期研究我们应用LncRNA芯片筛选到DN差异表达的LncRNA-IMP，在高糖刺激足细胞、临床DN患者和DN小鼠肾组织中验证LncRNA-IMP均高表达，上调LncRNA-IMP表达能抑制足细胞线粒体自噬，促进足细胞损伤的发生；生物信息学和RNA pull-down实验筛选到LncRNA-IMP与线粒体自噬激活相关蛋白FUNDC1结合。因此本项目提出假说：DN时LncRNA-IMP通过与FUNDC1结合，介导FUNDC1沉默，抑制线粒体自噬，进而促进足细胞损伤。本项目拟进一步证实LncRNA-IMP与FUNDC1结合，并探讨对FUNDC1功能沉默、足细胞线粒体自噬和足细胞损伤的影响，深入研究LncRNA-IMP-FUNDC1-线粒体自噬-足细胞损伤相互作用，为DN防治探索新靶点。

Podocyte injury plays a core role in the pathogenesis of diabetic nephropathy (DN). Alleviating podocyte injury can effectively inhibit the occurrence and progression of DN, however, the mechanism of podocyte injury is still not clear. In our previous study, we screened the differential expression of LncRNA-IMP in DN by the application of LncRNAs microarray technology. The high expressions of LncRNA-IMP were validated in the high glucose-stimulated podocytes and renal tissue of DN mouse and patients. The upregulation of LncRNA-IMP expression can inhibit mitophagy in podocytes and promote podocyte injury. FUNDC1, a protein closely related to mitophagy activation, was screened to bind with LncRNA-IMP through bioinformatics and RNA pull-down experiment. Therefore, we propose a hypothesis that LncRNA-IMP binds to FUNDC1 and mediates FUNDC1 silencing, which inhibits FUNDC1-dependent mitophagy and then promots podocyte injury in DN. In this project, we will further plan to make a multidimensional study by using animal models of DN, podocyte injury models induced by high glucose and molecular level, which will focus on the role of LncRNA-IMP-FUNDC1-mitophagy in the podocyte injury of DN. This project aims to elucidate the new mechanism of podocyte injury and explores a new target for clinical prevention and treatment of DN.