基于DcR2靶向清除衰老肾小管上皮细胞防治糖尿病肾病的作用及机制

细胞应激衰老是应激引发与增龄无关的细胞周期停滞，通过释放衰老相关分泌表型（SASP）和抑制细胞增殖与再生，导致组织器官不可逆损伤、功能丢失和修复障碍。肾小管细胞应激衰老是糖尿病肾病（DN）不可逆进展的重要机制，是导致肾组织炎症与纤维化、肾功能损害最主要的原因之一。我们前期研究证实衰老肾小管细胞特异性标志DcR2介导了衰老细胞凋亡抵抗，与DN肾组织损伤及肾功能损害密切相关。本项目拟用诱导性DcR2基因敲除小鼠构建DN模型，探索DcR2靶向清除衰老肾小管细胞对肾组织炎症、纤维化的抑制和促进组织细胞修复的作用，验证TRAIL-DR5信号促进了衰老肾小管细胞凋亡从而清除衰老细胞。本项目首次提出并证明基于DcR2靶向清除衰老肾小管细胞在防治DN进展中的作用及机制，为未来防治DN进展的新策略奠定了理论基础。

Stress-induced senescence is an arrest of cell cycle which is caused by stress and it isn’t related to age. Senescent cell can result in irreversible damage, dysfunction and repair obstacles in organs via releasing senescence-associated secretory phenotype (SASP) and inhibiting cell proliferation and regeneration. Renal tubular cell senescence is a critical mechanism in the irreversible progression of diabetic nephropathy (DN), and it is one of main reasons for leading to renal inflammation and fibrosis and renal function damage. Our previous studies proved that DcR2 was a specific marker of senescent renal tubular cells, and it mediated apoptotic resistance. Renal DcR2 was associated with renal tissue injury and function damage. This project aims to investigate the role of inhibiting renal inflammation and fibrosis and promoting tissue repair by targeted clearance of senescent renal tubular cells basing on DcR2 with inducible DcR2 gene knockout mice. And verify TRAIL-DR5 signaling promoting apoptosis of senescent renal tubular cells. We firstly investigate the role and mechanism of targeted clearance of senescent renal tubular cells basing on DcR2 in the progression of DN. The project will lay a theoretical foundation for the new strategy in prevention and treatment of DN.