Analysis of FGF receptor signalling involved in lens cell proliferation and differentiation

白内障，即眼睛透镜失去透明度，是世界上致盲的主要原因。白内障的最终治愈取决于更好地了解正常晶状体和白内障透镜中的基本分子过程。我们的研究集中在识别控制透镜形成和维持的分子上。生长因子是细胞行为的重要调节因子，我们的研究提供了令人信服的证据表明，FGF生长因子家族成员通过影响透镜细胞增殖和分化在透镜发育生物学中发挥关键作用。我们实验室的一个重要发现是FGF在不同浓度下诱导透镜上皮细胞增殖和分化。FGF在结合并激活细胞表面FGF受体（FGFR）后引发细胞内应答。FGFR是膜结合酪氨酸激酶，其在活化时活化导致特异性细胞应答的特异性信号传导途径。为了了解FGF如何介导和调节透镜细胞中的不同反应，即细胞增殖和纤维分化，我们计划使用将在转基因小鼠晶状体中特异性表达的遗传改变的FGFR来检查FGFR在正常透镜发育中的作用。虽然已知四种不同的FGF受体基因由正常发育的透镜表达，但不知道这些基因中的每一种在透镜细胞增殖和分化过程中起什么作用。此外，由于我们可以在体外重现特定FGF诱导的透镜细胞反应，因此我们将使用我们的透镜外植体培养系统来剖析特定受体激活下游的信号传导途径，并将其与特定细胞反应相关联。通过识别控制正常透镜发育所必需的细胞过程的分子和机制，我们可以更好地理解这些过程的中断如何导致白内障形成。

Cataract, the loss of transparency of the eye lens, is the leading cause of blindness in the world. An eventual cure for cataract depends on a better understanding of the basic molecular processes in the normal and cataractous lens. Our research has focussed on identifying the molecules that control the formation and maintenance of the lens. Growth factors are important regulators of cell behaviour and our studies have provided compelling evidence that members of the FGF growth factor family play pivotal roles in lens developmental biology by influencing lens cell proliferation and differentiation. An important finding from our laboratory is that FGF induces lens epithelial cell proliferation and differentiation at different concentrations. The FGFs elicit intracellular responses upon binding to and activating cell surface FGF receptors (FGFRs). The FGFRs are membrane bound tyrosine kinases which upon activation, activate specific signalling pathways leading to a specific cellular response. To understand how FGFs mediate and regulate different responses in lens cells, namely cell proliferation and fibre differentiation, we plan to examine the role of FGFRs in normal lens development using genetically altered FGFRs that will be expressed specifically in lenses of transgenic mice. While it is known that four different FGF receptor genes are expressed by the normal developing lens, it is unknown what role each of these play in the process of lens cell proliferation and differentiation. In addition, as we can reproduce a specific FGF-induced lens cellular response in vitro, we will use our lens explant culture system to dissect the signalling pathway(s) downstream from specific receptor activation and correlate this with a specific cellular response. By identifying the molecules and mechanisms that control the cellular processes essential for normal lens development, we can better understand how disruptions of these processes lead to cataract formation.