FGF-1通过介导胰岛素抵抗和炎症反应作用于糖尿病肾病的机制研究

TZDs-PPARγ-FGF1信号轴在糖尿病中的关键调节作用以及肾病病人肾组织中FGF1特异性高表达使我们意识到FGF1不仅对糖尿病而且对其并发的肾病也具有潜在的治疗作用。而且，在考察FGF1对2型糖尿病作用机制时，我们已初步观察到FGF1给药组的肾脏功能要显著好于模型组，基于此，本课题将进一步深入研究FGF1对糖尿病肾病的确切作用并重点验证两个理论假设：1）由于肝素位点的敲除仅会降低FGF1促有丝分裂作用但对其内分泌功能无影响，本课题将进一步研究和验证FGF1对糖尿病并发症的调节作用同样是不依赖于肝素结合位点，这将为设计更安全的糖尿病肾病药物提供理论依据；2）由于FGF1对1型糖尿病无降糖作用，本课题将同时考察FGF1对1型和2型糖尿病肾病的作用，以得出FGF1是否能通过胰岛素增敏和缓解机体炎症直接发挥对糖尿病肾病的干预作用，这将有助于提高人们对FGF1在糖尿病并发症中作用机制的认识。

Recent research demonstrated that TZDs-PPARγ-FGF-1 axis plays the important role in diabetes and finding also showed that FGF-1 was over-expression in renal of nephropathy patients. Therefore, it is considered that FGF-1 possesses both potential improvement of diabetes and its complication. Our preliminary data showed FGF-1 treatment has better renal protection compared with db/db model group. In this study we will focus on systematically studying the regulation of FGF-1 in diabetic nephropathy and verifying two theoretical hypothesis: 1) Because of heparin binding mutation can retain the endocrine function of FGF-1, in this study, we propose that the intervention and treatment of FGF-1 in diabetic nephropathy is also independent on heparin-binding ability of FGF-1. This will provide theoretical guidance of R&D of new diabetic nephropathy drugs. 2) FGF-1 has no hypoglycemic effect in type 1 diabetes, so we will investigate the effect of FGF-1 in both type 1 and type 2 diabetic nephropathy and test whether FGF-1 plays the direct role in diabetic nephropathy included insulin sensitivity and inflammation. This work will extend our knowledge about the role and mechanism of FGF-1 in diabetic complications.