非促分裂型FGF-1通过介导氧化应激作用治疗肾病的机制研究

氧化应激反应在肾病的发生发展中扮演着非常重要的角色。团队前期的研究成果已重点阐明FGF1通过抑制炎症反应治疗糖尿病肾病的分子机制，但FGF1存在一定的促增殖风险。因此，申请人基于FGF1与FGFR1的作用方式及其晶体结构，首先构建了安全性更高的非促分裂型FGF1-HS-。基于前期的报道及研究基础，本项目主要提出两个假设：1）除了对糖尿病肾病，FGF1-HS-可能能独立于降糖，对其他类型的肾病也有干预和治疗作用。2）FGF1-HS-可能是直接干预氧化应激反应而发挥对肾脏保护作用。因此，本项目将从细胞和动物水平出发，采用糖尿病肾病和阿霉素肾病两模型，来考察FGF1-HS-对肾病的治疗作用，重点研究并阐明氧化应激反应在FGF1-HS-改善肾病的相关分子机制。以上假设的验证，将有助于人们对FGF1在肾病中的作用及其机制产生较为全面的认识，同时为指导开发安全有效的肾病治疗药物提供充实的理论指导。

Oxidative stress plays an important role in the development of diabetic nephropathy and other kidney diseases. FGF1 can ameliorate diabetic nephropathy that is independent of blood glucose.However, it has a certain proliferation activity, so based on the FGF1 and heprin structure, we firstly designed and purified the non mitogen FGF1 (FGF1-HS-) with higher safety. In this study we will focus on systematically studying the regulation of FGF-1-HS- in nephropathy and verifying two theoretical hypothesis: 1) whether FGF-1-HS- plays an important role in the prevention oxidative stress besides anti-inflammatory effect. 2) Based on the intervention of FGF-1-HS- on oxidative stress and inflammation, whether FGF-1-HS- has a potential therapeutic effect on other types of nephritis. We will investigate the effect of FGF1-HS- on diabetic nephropathy and doxorubicin nephropathy at the cell and animal level, so as to find out whether FGF1-HS-can directly play an intervention role in kidney disease through regulating oxidative stress. This work will extend our knowledge about the role and mechanism of FGF-1 in nephropathy.