细胞应激衰老是糖尿病肾病（DN）的重要病理基础，但其发病机制不清。Parkin是一种泛素化连接酶，其高表达能显著延长果蝇寿限。Parkin基因突变是早发型老年痴呆、帕金森病的遗传因素。我们前期研究发现DN患者肾组织中衰老标志P16阳性肾小管细胞Parkin表达降低，过表达Parkin能够抑制高糖诱导的细胞应激性衰老，提示Parkin可能是一种抗衰老因子，在DN发生发展中扮演着重要角色。本项目拟研究DN时Parkin调控细胞周期和衰老相关分泌表型（SASP）的作用；并采用过表达载体、shRNA及CRISPR/Cas9系统等技术调控Parkin及下游信号分子表达，证明Parkin分别通过P53 、GATA4途径调控细胞周期和SASP而促进DN疾病进展。本项目首次提出并证明Parkin作为潜在的抗衰老因子，在DN进展中具有重要作用，为以抗细胞应激性衰老治疗 DN奠定理论基础。

Stress-induced senescence plays a fundamental role in the pathogenesis of diabetic nephropathy (DN). However its mechanism is not well defined. Up-regulation of Parkin, an ubiquitin ligase, can significantly extend the lifespan of Drosophila. Mutation of Parkin is a prevalent genetic contributor to early onset Parkinson's disease and Alzheimer's disease. Our previous result showed that Parkin expression was decreased in p16 positive renal tubular cells in DN patients. In this project, we will study the role of Parkin in regulation of cell cycle and senescence associated secretory phenotype (SASP) through p53 and transcription factor GATA4 pathway, respectively. The over-expression vectors, siRNAs and CRISPR/Cas9 system will be used to regulate the expression of Parkin and its downstream signal molecules. Based on the study, we could propose that Parkin, as an anti-senescence factor, plays a key role in the development of DN and potentially provide a novel therapy for DN.