乳腺基质中FGF信号通路在乳腺发育中的作用研究

The role of the local microenvironment in influencing cell behavior is central to normal development. Understanding stromal biology in normal development and the mechanism by which its deregulation may promote tumorigenesis is of key importance. Mouse mammary gland is a powerful model for understanding the genetic and cellular basis of stromal biology. We newly found that receptor tyrosine kinase (RTK) signaling negative regulator- Sprouty gene knockout in stromal fibroblasts leaded to abnormal branching morphogenesis in mammary gland.Importantly, FGF signaling was found overactivated in Sprouty knocked out fibroblasts. Here, we hypothesize that FGF signaling in stroma is essential for mammary development. The specific aims are: 1. To observe whether FGF signaling in stroma regulates mammary gland morphogenesis. 2. To determine how FGF signaling in stroma regulates epithelium behavior 3. To determine how FGF signaling in stroma regulates the function of firbroblasts. 4. To explore whether there is a FGF signaling functional loop between epithelium and stroma. Together, the current study will be the first study focusing the effect of FGF signaling in stroma on Mammary gland development. It may provide valuable insight into the role of FGF signaling in breast development and contribute to fully understand the role of the local microenvironment in influencing cell behavior, and also the interaction mechanism between epithelium and stroma during normal development and tumor.formation.

细胞微环境对细胞行为的影响是发育生物学研究的重要方面。基质构成上皮细胞微环境，参与脊椎动物器官发生及肿瘤形成。小鼠乳腺是基质功能及机理研究的良好模型。我们发现，将乳腺基质成纤维细胞中受体络氨酸激酶（RTK）信号通路的负调控因子-Sprouty基因敲除后，乳腺上皮分支形态异常，成纤维细胞中FGF信号通路活化上调。提示基质中的FGF信号通路可能调控乳腺形态发生。本课题利用条件性基因敲除小鼠及体外器官培养等关键技术，探索基质中FGF信号通路对乳腺发育的影响。首先，观察成纤维细胞中FGFR敲除后乳腺的形态变化；然后，分别探索对乳腺上皮及成纤维细胞功能的影响；最后探究上皮和基质之间是否存在FGF信号通路的相互调节。该研究首次关注到基质中FGF信号通路的作用，对全面揭示FGF信号通路在乳腺发育中的功能，进一步明确细胞微环境调控乳腺发育的机制，了解上皮-基质之间的相互作用具有重要意义。

细胞微环境对细胞行为的影响是发育生物学研究的重要方面。基质构成上皮细胞微环境， 参与脊椎动物器官发生及肿瘤形成。本研究利用体外器官培养、三维立体细胞共培养等技术，证实了FGFR信号通路对乳腺成纤维细胞的功能产生影响；证实了乳腺成纤维细胞中FGFR1和FGFR2受体起到主要的作用；利用基质中FGFR特异性敲除小鼠证实FGFR1敲除后导管变细；而FGFR1;FGFR2敲除后乳腺发育延迟。利用三维立体细胞共培养，发现成纤维细胞中FGFR敲除可以通过影响糖酵解，进而影响乳腺上皮干细胞的行为。该研究证实了乳腺基质中的FGFR信号对乳腺上皮发育的影响。该研究首次关注到基质中FGF信号通路的作用，对全面揭示FGF信号通路在 乳腺发育中的功能，进一步明确细胞微环境调控乳腺发育的机制，了解上皮-基质之间的相互 作用具有重要意义。