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

白内障，即眼睛晶状体透明度的丧失，是世界上导致失明的主要原因。白内障的最终治愈取决于对正常晶状体和白内障晶状体中基本分子过程的更好理解。我们的研究集中在识别控制晶状体形成和维持的分子。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，表明成纤维细胞生长因子家族成员通过影响晶状体细胞的增殖和分化在晶状体发育生物学中发挥关键作用。本实验室的一个重要发现是，在不同浓度下，成纤维细胞生长因子都能诱导晶状体上皮细胞的增殖和分化。FGFs与细胞表面成纤维细胞生长因子受体(FGFRs)结合并激活后，可引起细胞内反应。FGFRs是膜结合的酪氨酸激酶，一旦激活，就会激活特定的信号通路，导致特定的细胞反应。为了了解FGFs如何调节晶状体细胞的不同反应，即细胞增殖和纤维分化，我们计划使用转基因小鼠晶状体中特异表达的FGFRs来研究FGFRs在正常晶状体发育中的作用。虽然已知在正常发育的晶状体中表达四种不同的成纤维细胞生长因子受体基因，但尚不清楚它们在晶状体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复制成纤维细胞生长因子诱导的特定晶状体细胞反应，我们将使用我们的晶状体外植体培养系统来剖析特定受体激活下游的信号通路(S)，并将其与特定细胞反应相关联。通过识别控制正常晶状体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是如何导致白内障的形成。

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.