REGULATION OF OCULAR LENS DEVELOPMENT BY GROWTH FACTORS

晶状体是研究哪些因素控制的模型组织 哺乳动物的发育。私家侦探和其他人已经开始发现 调节正常的细胞内和细胞外因子 这种上皮组织的形态发生。目前这笔赠款的目标是 应用是继续我们的努力来定义分子 调节晶状体发育的途径。通过一个 转基因和基因打靶方法学的结合， 视网膜母细胞瘤易感基因产物Rb已被证明是 在调节植物的末端分化过程中起关键作用。 鼠标镜头。Rb失活导致细胞异常增殖和 伴随而来的晶状体房室内细胞凋亡的诱导 在正常情况下，细胞退出细胞周期并经历 具体的差异化方案。在这种差异化中 程序，包括细胞核和线粒体在内的细胞器丢失，而 保持了细胞的完整性。一系列事实导致了 假设晶状体细胞中的核丢失可能通过 与程序性细胞死亡相关的机制。在这件事上 资助提案PI描述了解决以下问题的实验： 这个假说。Rb蛋白被认为是调节细胞 至少部分地通过它对转录的调节来进行 因子，E2F。证据表明N-myc，一种E2F的潜在作用 反应基因，在调节Rb对晶状体发育的调节中。 PI将进行实验，以解决N-myc的重要性。 最后，PI和其他人利用转基因来探索 成纤维细胞生长因子，成纤维细胞生长因子，成纤维细胞生长因子-1和成纤维细胞生长因子-2，促进晶体发育。 这些细胞外因子被认为在空间上调节了 晶状体终末分化的限制性诱导。全球 大鼠晶状体中成纤维细胞生长因子信号通路的破坏 晶状体发育，证明了这些生长的重要性 各种因素。更多的实验表明，成纤维细胞生长因子-2是一种 在镜头中过度表达的因素。PI将检验这一假设 成纤维细胞生长因子-2通过多种因素的结合决定晶状体纤维细胞的命运 转基因和有针对性的基因敲除策略旨在干扰 成纤维细胞生长因子-2的功能是消除其在眼睛中的表达来源。

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.