FGF-1体内双重调节功能及其在内分泌系统中的作用机制研究

作为成纤维细胞生长因子FGF家族的重要成员,FGF-1在旁分泌系统中的促细胞增值功能为人熟知，但随着TZDs-PPARγ-FGF-1信号轴在内分泌系统中关键调节作用的报道以及本课题组前期对FGF-1显著促进脂肪细胞糖吸收和降低db/db小鼠血糖水平的发现，让人们逐渐认识到FGF-1具有旁分泌和内分泌双重调节功能。而且我们还发现无论是降低FGF-1与受体结合能力还是去除其促分裂所必须依赖的肝素结合位点，其内分泌作用都能完好保留。这就给出一个重要启示，即FGF-1双重调节功能与其激活受体及下游信号强弱存在某种内在平衡关系。本课题将首先在分子水平验证这一创新理论，进而系统研究FGF-1及其非促分裂型突变体在糖尿病中的具体作用及优势，并进一步阐明发挥内分泌调节作用深入的分子机制。通过该项目的实施，将会有助于提高人们对FGF-1及其类似家族成员作用的新认识并指导创新型糖尿病治疗药物的优化设计和开发。

FGF-1, one of the important FGFs members, is well known mitogen capable of potently stimulating proliferation of cells. Recent research demonstrated that FGF-1 is TZDs-PPARγ-FGF-1 axis plasy the important role in endocrine system and our finding also showed that FGF-1 was beneficial to reduce the glucose level of db/db mice. Therefore, it is considered FGF-1 possesses both mitogenic and metabolic activities. Our preliminary data showed that whatever N-terminal truncated FGF-1 or heparin binding mutation can retain the full metabolic effect compared with wild-type FGF-1. So we can propose that quantitative differences in the strength of FGF-FGFR binding and dimerization dictate proliferative and metabolic activity specifically, mitogenic activity requires strong FGF-FGFR binding and persistent dimerization whereas a metabolic response can be achieved by a more transient dimerization. We decided to test this hypothesis using FGF-1 and its non-mitogenic mutants in cell or molecular level. Then we will focus on systematically studying the metabolic effects of FGF-1 in vivo and achieve the mechanism behind this novel function. This study will extend our knowledge about FGF-1 and offer the new idea for design and development of new diabetes drugs.