肾脏是人体衰老过程中变化最为明显的器官之一。在肾脏疾病的发生发展中，衰老又使肾脏固有细胞易感，反馈性地加速肾脏衰老进程。其中足细胞损伤/衰老—肾小球硬化—肾功能下降是肾脏衰老的轴心。因此深入研究足细胞衰老与损伤的机制，寻找有效的药物靶点，具有重要的意义。G蛋白偶联受体（GPCRs）是人体内最大的膜受体蛋白家族，在细胞信号转导和生理功能调控中发挥重要作用，也是最成功的一类药物靶点。尽管研究表明足细胞GPCR信号途径可能参与了肾脏衰老的调控，但机制尚不清楚。本课题将从肾脏衰老和潜在治疗靶标发现的角度，以足细胞为中心，鉴定衰老相关足细胞GPCRs，深入解析GPCRs在肾脏衰老轴心进程中的关键作用及其在肾脏疾病易感性中的意义，并进一步阐明乙酰化表观遗传修饰在足细胞GPCRs调控肾脏衰老中的作用。该研究将有助于阐明肾脏衰老及向退行性变化演变的机制，为寻找延缓肾脏衰老和治疗肾脏疾病的药物靶点提供思路。

Epidemiologic, clinical, and molecular evidence suggest that aging is a major contributor to the increasing incidence of acute kidney injury and chronic kidney disease. The aging kidney undergoes complex changes that predispose to renal pathology. The main clinical finding of renal aging is the decrease in glomerular filtration rate, and its structural correlate is the loss of functioning nephrons. Mechanistically, this has been linked to different processes, such as podocyte hypertrophy, glomerulosclerosis, tubular atrophy, and gradual microvascular rarefaction. As terminally differentiated cells, podocytes play a central role in renal aging. Podocyte proliferation and replacement capacity are minimal in the adult mouse under normal conditions. Therefore, podocyte inury/aging takes the center stage on the renal aging. The underlying molecular mechanisms of podocyte aging/injury could be the target of therapeutic strategies in the future. G protein-coupled receptors (GPCRs) participate in a variety of physiologic functions, and several GPCRs have critical physiologic and pathophysiologic roles in the regulation of renal function. Although recent studies have indicated that GRPCRs are involved in the regulation of podocyte function and renal aging, the molecular mechanisms keep unknown. In this project, we will investigate the role of the adhesion GPCR (aGRCR) family in podocyte aging/injury and renal aging and further identify the specific member of aGPCR responsible the renal aging. We also explore the contribution of the sirtuin (SIRT) family of class III NAD+-dependent histone deacetylases (HDACs)-mediated histone acetylation to GPCR-mediated podocyte aging/injury. Collectively, our studies will for the first time demonstrate that GPCR- SIRT network on the regulation of renal aging. Pharmacological targeting of these signaling pathways at multiple levels may provide novel strategies of senotherapy with the goal of reducing the number of senescent podocytes to decrease aging-related disease in the kidney.