糖尿病相关肾脏疾病已成为我国慢性肾脏疾病的首要病因，足细胞脂质代谢紊乱参与了糖尿病肾病的发生和发展。最新临床研究报道卷曲螺旋结构域蛋白CCDC92是冠心病和2型糖尿病共同的风险基因，但其生物学功能尚不清楚。我们前期实验发现CCDC92在糖尿病肾病足细胞损伤中扮演重要角色，但机制不明。本课题将通过足细胞特异性基因敲除小鼠、体外培养足细胞和临床切片，借助形态学、细胞和分子生物学、免疫电镜、流式细胞术、激光共聚焦、同位素标记等方法明确在糖尿病肾病过程中，CCDC92通过增加足细胞中蛋白酶体在中心体的聚集，增强泛素/蛋白酶体系统的活性，增加细胞内胆固醇外排酶ABCA1的降解，引起胆固醇累积，造成脂毒性损伤，且该作用受到NOX4介导的氧化应激通路的调控。本课题将对糖尿病肾病的病理生理机制和CCDC92的生物学功能进行补充，并为临床寻找延缓糖尿病肾病进展的有效策略提供新的靶点与研究基础。

Recent epidemiological evaluation report shows that the hospitalized population with chronic kidney disease related to diabetes has become the first cause for chronic kidney disease. Increasing evidences indicate that podocyte lipotoxicity is critical for the occurrence and development of diabetic kidney disease (DKD). The latest clinical research shows that coiled-coil domain containing protein 92 (CCDC92) is a common risk gene for coronary heart disease and type 2 diabetes, while the biological function of CCDC92 is unknown till now. Our preliminary studies suggested that CCDC92 might play an important role in podocyte injury and lipid metabolism in diabetic kidney disease, but the mechanism is not yet understood. In this study, we will use podocyte specific knockout mice, cultured human podocytes and clinical renal biopsy sections to investigate the role of CCDC92 on podocyte lipotoxicity in diabetic kidney disease by various methods of morphology, cellular and molecular biology, immunoelectron microscopy, flow cytometry, confocal as well as isotope labeling. Moreover, we are going to demonstrate that the mechanism of this effect is partly through increasing the proteasome subunits accumulation on the cellular centrosome, which may activate ubiquitin proteasome system subsequently. As a sequence, the ATP-binding cassette transporter A1 (ABCA1) protein which mediates the cholesterol efflux from cell will be decreased by the ubiquitin-proteasome-mediated degradation, resulting in cholesterol accumulation and therefore inducing the podocyte injury. We also intend to demonstrate that the effect of CCDC92 in podocyte lipotoxicity is regulated by NADPH oxidase NOX4 mediated oxidative stress. Our study may enrich the pathophysiologic mechanisms of diabetic kidney disease, add new results for the signal pathway of podocyte lipotoxicity,supply more informations for the biological function of CCDC92 as well . Furthermore, our work may provide a new viewpoint for the potential theraputic methods of slowing the progress of diabetic kidney disease in the future.