REGULATION OF OCULAR LENS DEVELOPMENT BY GROWTH FACTORS

透镜是研究哪些因素控制的模型组织 哺乳动物的发育 PI和其他人已经开始确定 调节noraml的细胞内和细胞外因子 这种上皮组织的形态发生。 本次赠款的目标是 应用是继续我们的努力，以确定分子 调节透镜发育的途径。 通过 转基因和基因靶向方法学的组合， 视网膜母细胞瘤易感基因产物Rb已被证明是 在调节终末分化过程中起关键作用， 鼠标透镜。 Rb的失活导致异常的细胞增殖， 在透镜的隔室中伴随诱导细胞凋亡 在正常情况下，细胞退出细胞周期， 具体的分化方案。 在这种分化中， 程序，包括细胞核和线粒体在内的细胞器丢失， 细胞完整性得以维持。 一些事实导致了 假设透镜细胞中的细胞核丢失可能通过 与程序性细胞死亡相关的机制。 在这 授予提案PI描述实验，以解决的有效性 这个假设。 Rb蛋白被认为是调节细胞 至少部分是通过其对转录的调节来进行的 因子，E2 F。 证据表明N-myc的潜在作用，E2 F 反应基因，介导Rb对透镜发育的调控。 PI将进行实验以说明N-myc的重要性。 最后，PI和其他人已经使用转基因来探索 成纤维细胞生长因子FGF-1和FGF-2在晶状体发育中的作用。 这些细胞外因子被认为是介导 限制了透镜中终端分化的诱导。 全球 透镜中FGF信号传导途径的破坏， 透镜的发展，证明了这些增长的重要性 因素 另外的实验表明，FGF-2是一种“存活”因子， 当在透镜中过表达时， PI将检验假设 FGF-2通过以下因素的结合决定了透镜纤维细胞的命运 转基因和靶向敲除策略，旨在干扰 FGF-2的功能是消除其在眼内的表达来源。

The lens is a model tissue for studying which factors control mammalian development. The PI and others have begun to identify intracellular and extracellular factors that regulate the noraml morphogenesis of this epithelial tissue. The goals of this current grant application are to continue our efforts to define the moleccular pathways by which lens development is regulated. Through a combination of transgenic and gene targeting metholologies, the retinoblastoma susceptibility gene product, Rb, has been shown to be critical in regulating the process of terminal differentiation in the mouse lens. Inactivation of Rb led to aberrant cell proliferation and concomitant induction of apoptosis in the compartment of the lens where normally cells withdraw from the cell cycle and undergo a specific program of differentiation. In this differentiation program,organelles including nuclei and mitochondria are lost, while celluar integrity is maintained. A number of facts have led to the hypothesis that loss of nuclei in lens cells may occur through a mechanism related to that seen in programmed cell death. in this grant proposal the PI describes experiments to address the validity of this hypothesis. The Rb protein is though to regulate cellular processes at least in part through its modulation of the transcription factor, E2F. Evidence points to the potential role of N-myc, an E2F responsive gene, in mediating Rb's regulation of lens development. The PI will perform experiments to address the importance of N-myc. Lastly, the PI and others have used transgenesis to explore the role of the fibroblast growth factors, FGF-1 and FGF-2, inlens development. These extracellular factors are though to mediate the spatially restricted induction of terminall differentiationin the lens. Global disruption of the FGF signaling pathways in the lens to gross defects in lens development, demonstrating the importance of these growth factors. Additional experiments suggest that FGF-2 is a 'survival factor' when overexpressed in the lens. The PI will test the hypothesis that FGF-2 determines the fate of lens fiber cells by a combination of transgenic and targeted knockout strategies designed to interfere with FGF-2 function of eliminate its source of expression in the eye.