糖尿病肾病病理生理机制未明，足细胞胰岛素抵抗参与了该病的发生发展，而最新研究表明DGKε已成为研究肾脏疾病的重要靶标。我们的前期工作发现DGKε可能在糖尿病肾病足细胞胰岛素抵抗中扮演重要角色，但机制不明。本课题将应用细胞、动物模型及临床标本，借助体内外转染技术，通过形态学、细胞和分子生物学、免疫共沉淀、膜片钳、流式细胞术、激光共聚焦、Pull-Down等方法明确在糖尿病肾病过程中，DGKε能够改善足细胞胰岛素抵抗，进一步证明该作用是通过调控SNARE复合体介导的GLUT4囊泡运输实现的，从而建立糖尿病肾病→DGKε↓→Rho蛋白→SM蛋白↓→SNARE复合体↓→GSV 囊泡运输↓→GLUT4膜转位↓→胰岛素抵抗→足细胞损伤的信号转导通路。本课题将为充实糖尿病肾病的病理生理机制、阐明糖尿病肾病足细胞损伤的信号转导途径增加新的研究基础，并为临床寻找糖尿病肾病有效防治措施提供新的思路。

Despite evidence from multiple clinical and experimental studies, the pathogenesis of diabetic nephropathy is not yet fully understood.Recently reports indicate that podocyte insulin resistance is critical for the production of large amount of proteinuria which contribute to the devolepment of diabetic nephropathy. Diacylglycerol kinase ε (DGKε) is considered as a new target for the research work on kidney diseases according to the latest study. Our preliminary study suggested that DGKε may play an important role in podocyte injury and insulin resistance in diabetic nephropathy，but the mechanism is not yet understood. In this study, we will use various methods of morphology, cellular and molecular biology, GTPase Pull-Down，patch clamp，flow cytometry, Co-IP and confocal to investigate the role of DGKε on podocyte insulin resisitance in diabetic nephropathy by means of both in vivo and in vitro transfection techniques, together with clinical kidney sections. Moreover, we are going to demonstrate that the mechanism of this effect is partly through activating GTPase, Rho protein, then regulating the activity of soluble N-ethylmaleimide -sensitive factor-attachment protein receptor (SNARE) complex regulating protein, Sec/Munc18 like proteins (SM protein), which may in turn increase the stability of SNARE complex to improve the memberane transloction of glucose transporters 4 (GLUT4) from GLUT4 storage vesicles (GSV). In the end, we are aiming at establishing such a signal transduction pathway as diabetic nephropathy →DGKε↓→GTPase Rho protein→SM protein↓→SNAREcomplex↓→GSV vesicle trafficking↓→GLUT4 membrane transloction↓→podocyte insulin resisitance→podocyte injury. Our study may enrich and improve the pathophysiologic mechanisms of diabetic nephropathy, add new results for the signal transduction pathway of podocyte insulin sensitivity. Moreover, our work may provide a new viewpoint for both the basic and clinical research on the pathogenesis and the potential theraputic methods of diabetic nephropathy in the future.