FGF受体可溶性胞外段抑制肺纤维化的机制研究

There is one kind of protein in human body named soluble FGF receptor(sFGFR) which just contains the ectodomain of FGF receptor. TGF-β plays a central role in fibrosis, meanwhile accompanied by strongly enhanced FGF-2 signal. The results of our previous study showed that sFGFR2c could alleviate dramatically bleomycin-induced pulmonary fibrosis in mice through inhibiting FGF-2 signal, the differentiation of myofibroblasts and the expression of genes related to promoting ECM deposit. In the light of this, we presented a new theory hypothesis: FGF-2 is one of the key factor in the differentiation of myofibroblasts, sFGFR2c is able to down-regulate the expressions of a series of pro-fibrotic genes includingα-SMA through blocking FGF signal（also blocking TGF-βsignal through signal-pathway crosstalk ) , and exert its inhibitory effect on lung fibrosis.We are going to analyze the molecular mechanism of sFGFR2c on blocking FGF-2 signal from three aspects: binding to extracellular ligands, binding to cytomembrane receptor, endocytosis and nuclear translocation by protein interaction technique. Also using gene chip, molecular blocking, and other cellular and molecular techniques, we will explore the regulatory mechanism of sFGFR2c and FGF-2 on the expressions of α-SMA、E-Cadherin and other pro-fibrotic genes, observe their effects on apoptosis and EMT of AECⅡcells, in order to make clear the molecular mechanism of inhibitory effect of sFGFR2c on lung fibrosis and the role of FGF-2 in this process.The rationalization of the proposed hypothesis will be validated in vivo. This research will provide theoretical basis for a new method of controlling pulmonary fibrosis， and establish a pharmacological foundation for exploitation of correlative new drugs.

人体有一类只含FGF受体胞外段的蛋白即可溶性FGF受体（soluble FGFR，sFGFR），前期的研究表明sFGFR2c可通过抑制FGF-2信号，成肌纤维细胞分化及促基质沉积的基因的表达，显著抑制小鼠博来霉素诱导的肺纤维化。为此我们提出新的理论假设： FGF-2是关键的促成肌纤维细胞分化因子，sFGFR2c可通过抑制FGF信号下调如α-SMA等多个促纤维化基因的表达抑制肺纤维化。我们将采用蛋白质相互作用技术通过胞外、胞膜及内吞进核等层面分析sFGFR2c对FGF-2信号的抑制，采用基因芯片、分子阻断、细胞和分子生物学技术探讨sFGFR2c和FGF-2对α-SMA、E-Cadeherin等基因的表达调控，观察其对AECⅡ细胞凋亡和EMT的影响，以明确二者在肺纤维化中作用的分子机制，并在在体水平验证上述假设的合理性。本研究将为调控肺纤维化的新方法提供理论依据，为相关新药开发打下药理学基础。

特发性肺纤维化 (idiopathic pulmonary fibrosis，IPF)是一种原因不明,病理改变以普通型间质性肺炎为特征的慢性间质性肺部疾病。IPF病人平均生存时间低于3-5 年，生存率为30%～50%，迄今，其发病机制还并不清楚，因此对肺纤维化尚没有一种令人满意的治疗方法。我们通过对FGF-2在肺纤维化中作用的研究，发现TGF-beta是肺纤维化的驱动因子，它可以迅速提高成纤维细胞（FB）的FGF-2以及FGF受体的表达，并通过FGF信号促进FB的增殖以及FB向肌成纤维细胞（MB）的转化，同时肺泡正常功能依赖AECII细胞的修复作用，TGF-beta以及CTGF、FGF-2具有强大的促进AECII细胞发生EMT的作用，进一步促进了肺纤维化的发生和发展。在此过程中TGF-beta以及CTGF都可以激活并通过FGF-2信号通路而发挥作用，因而可溶性FGFR2c受体即FGFR2c的胞外段（包括突变型可溶性FGFR2c和野生型可溶性FGFR2c）通过抑制FGF-2的信号传导而具有很好的抑制肺纤维化作用，相关的分子机制研究已完成，部分成果已发表论文或正在投稿。此外我们还完成了msFGFR2c与膜上受体特异性结合的机制研究以便肿瘤的分子分型，阐明了msFGFR2c对肿瘤抑制作用的机制并发表了论文。此外我们还研究了其他亚型FGF受体胞外段的治疗痤疮的作用，并获得药监局化妆品许可已进入市场。相关研究申请了多项专利。从目前的研究的成果看，FGF受体胞外段的新药创制研究具有宽阔的前景，在肿瘤、纤维化、炎症性皮肤病、皮肤免疫等方面均具有重要的治疗潜力。(另一项研究发现BMP-2同时下调Rb上调CD44促进乳腺癌的迁移和干性，已投稿cell research）