Ras & PI 3-Kinase Signaling in Lens Development

描述(申请人提供)：晶状体细胞增殖和 分化受到精确调控，以实现正常的结构 镜头。据认为，眼球介质中存在的生长因子 控制晶状体的生长和发育。目前，我们对此知之甚少。 晶状体发育中的生长因子信号事件。在大多数细胞类型中， 与其受体结合的生长因子将触发受体酪氨酸激酶 激活RAS的活性，RAS是一种小的GTP结合蛋白。RAS的功能是 通过将上行信号传输到各个下行的继电器开关 效应器。我们的总体假设是RAS及其下游效应器，Raf 激酶和磷脂酰肌醇3-激酶(PI-3-Kinase)在细胞周期中发挥重要作用。 镜头显影。因此，我提出了以下具体目标：1)测试 Ras/Raf/MEK(MAP Erk Kinase)/Erk(细胞外配体调控) 激酶)途径控制晶状体细胞的增殖。2)确定PI的角色 晶状体细胞中3-激酶及其下游靶蛋白Akt/蛋白激酶B(PKB) 生死存亡。3)确定PI3-激酶在调节细胞大小和 纤维细胞分化过程中的形态。4)描述下游的特征 胰岛素受体底物-1激活的信号转导事件 转基因晶状体。这项拨款申请中提出的实验不能 仅为我们提供有关晶状体过程中信号机制的新信息 开发，但也可以建立体内模型来研究信号 发育系统中的转导途径。成功地开发了 晶状体上皮细胞增殖和存活的抑制物可能提供一种 后囊混浊(PCO)的有效治疗或预防 (也称为“后发性白内障”)。

DESCRIPTION (provided by applicant): Lens cell proliferation and differentiation are precisely regulated to achieve the normal structures of the lens. It is believed that the growth factors present in the ocular media control lens growth and development. Presently, we know very little about the growth factor signaling events in lens development. In most cell types, a growth factor binding its receptor will trigger the receptor tyrosine kinase activity which activates Ras, a small GTP-binding protein. Ras functions as a relay switch by transmitting the upstream signal to the various downstream effectors. Our overall hypothesis is that Ras and its downstream effectors, Raf kinase and phosphoinositide 3-kinase (PI 3-kinase), play important roles during lens development. Therefore, I propose the following specific aims: 1) Test whether the Ras/Raf/MEK (MAP Erk kinase)/Erk (extracellular ligand regulated kinase) pathway controls lens cell proliferation. 2) Determine the role of PI 3-kinase and its downstream target Akt/protein kinase B (PKB) in lens cell survival. 3) Determine the role of PI 3-kinase in regulating cell size and morphology during fiber cell differentiation. 4) Characterize the downstream signaling events of insulin receptor substrate-1 (IRS-1) activation in transgenic lens. The experiments proposed in this grant application can not only provide us new information on the signaling mechanisms present during lens development, but can also establish an in vivo model to study signal transduction pathways in a developmental system. Successful development of inhibitors for lens epithelial cell proliferation and survival may provide an effective treatment or prevention of posterior capsule opacification (PCO) (also called "after-cataract").