Ras & PI 3-Kinase Signaling in Lens Development

描述（由申请方提供）：透镜细胞增殖和 分化被精确地调节，以实现正常的结构， 透镜。据信存在于眼介质中的生长因子 控制透镜的生长和发育。目前，我们对它知之甚少。 透镜发育中的生长因子信号事件。在大多数细胞类型中， 生长因子结合其受体将触发受体酪氨酸激酶 活性激活Ras，一种小的GTP结合蛋白。RAS作为一个 通过将上行信号传输到各个下行信号， 效应器我们的总体假设是Ras及其下游效应子Raf 激酶和磷脂酰肌醇3-激酶（PI 3-激酶），在 透镜显影。因此，我提出以下具体目标：1）测试 Ras/Raf/MEK（MAP Erk激酶）/Erk（细胞外配体调节的 激酶）途径控制透镜细胞增殖。2)确定PI的角色 3-透镜细胞中Akt/蛋白激酶B（PKB）及其下游靶点 生存3)确定PI 3-激酶在调节细胞大小和 纤维细胞分化过程中的形态学。4)描述下游 胰岛素受体底物-1（IRS-1）激活的信号传导事件 转基因透镜。在这项拨款申请中提出的实验不能 仅为我们提供了关于透镜期间存在的信号机制的新信息 发展，但也可以建立一个体内模型，研究信号 发育系统中的信号转导途径。成功发展 透镜上皮细胞增殖和存活的抑制剂可以提供 有效治疗或预防后囊膜混浊（PCO） (also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").