SIRT5调控线粒体HSP60琥珀酰化修饰参与肾间质纤维化的分子机制研究

近端肾小管上皮细胞线粒体稳态失衡与肾间质纤维化密切相关。热休克蛋白60（HSP60）是线粒体内重要的分子伴侣蛋白，对维持线粒体结构和功能至关重要。HSP60受到多种翻译后修饰的调节。SIRT5是线粒体内重要的去琥珀酰化酶。我们体内体外预实验发现近端肾小管上皮细胞Sirt5敲除后HSP60琥珀酰化修饰水平增高、肾间质纤维化程度加重。因此，研究SIRT5调控HSP60琥珀酰化修饰在肾间质纤维化进程中的作用及机制具有重要意义。本项目以近端肾小管上皮细胞为研究对象，探讨琥珀酰化修饰对HSP60结构和功能的影响及HSP60琥珀酰化修饰在线粒体稳态和肾间质纤维化中的作用；同时利用近端肾小管Sirt5特异性敲除小鼠和Sirt5过表达小鼠，重点研究SIRT5对HSP60琥珀酰化修饰的调控作用，为深入认识肾间质纤维化和探索新的治疗靶点提供理论依据。

Mitochondrial dysfunction in proximal tubular epithelial cells is involved in the pathogenesis of renal interstitial fibrosis. Heat shock protein 60 (HSP60) is a chaperone and mainly located inside the mitochondria for protein folding purposes, preventing the aggregation of misfolded polypeptide clients while assisting during their refolding. HSP60 may be affected by post translational modifications (PTMs). Proximal tubular epithelial cells specific deletion of Sirt5, a mitochondrial desuccinylase, results in dramatic increases of HSP60 succinylation and severe renal interstitial fibrosis in vivo and vitro. Therefore, it is of great significance to explore the role of HSP60 succinylation in the process of renal interstitial fibrosis. This research will be set up as follows. Firstly, renal interstitial fibrosis models will be established, we will investigate the effect of succinylation on the structure and function of HSP60 and the role of HSP60 succinylation in mitochondrial homeostasis and renal interstitial fibrosis. Secondly, proximal tubular epithelial cells specific Sirt5 knockout mice and Sirt5 knock-in mice are used to explore the mechanism and the role of SIRT5 on HSP60 succinylation. This study will not only help us to understand the pathogenesis of renal interstitial fibrosis from the new perspective of PTMs, but also provide a new clue for the prevention and treatment of renal interstitial fibrosis.