Ras and Phosphoinositide 3-kinase Signaling in Lens Development

描述(申请人提供)：晶状体细胞的增殖、分化和存活受到严格的调控，以实现晶状体的正常发育模式和结构。生长因子可能是这些细胞事件的关键调节因子，但对晶状体中的生长因子信号通路知之甚少。RAS是生长因子受体酪氨酸激酶(RTKs)下游的一种小分子GTP结合蛋白，在生长因子信号转导中发挥重要作用。在上一次资助期间，我们证明了RAS在正常晶状体发育过程中是细胞增殖所必需的，但不是启动纤维细胞分化所必需的。其他研究人员已经证明，成纤维细胞生长因子受体(FGFRs)激活的信号对纤维细胞分化和晶状体细胞生存是必不可少的。在这次拨款申请中，我们将继续研究RTK-RAS信号通路在晶状体中的作用。在具体目标1和2中，建议进行实验以确定Sprouty和ERK在晶状体发育中的作用。Sprouty是RTK-RAS途径的负调控因子，ERK是RAS的下游效应因子。在特定的目标3中，我们将探讨FGFR信号缺陷在小鼠晶状体中诱导细胞死亡的机制。拟议中的实验将为阻止晶状体细胞增殖和消除晶状体中异常细胞的潜在方法提供进一步的见解。这些知识对于开发预防和治疗后囊混浊(PCO)的方法非常重要，PCO是白内障手术最常见的并发症。此外，这项工作的结果将扩大我们对生长因子信号在其他发育系统和疾病过程(如癌症)中细胞增殖和细胞生存的理解。本研究的目的是研究生长因子信号在发育中的小鼠晶状体中的作用。这一认识将有助于开发新的方法来预防和治疗后囊混浊(PCO)，后囊混浊是白内障手术最常见的并发症。

DESCRIPTION (provided by applicant): Lens cell proliferation, differentiation and survival are tightly regulated to achieve the normal developmental pattern and structure of the lens. Growth factors are likely the key regulators of these cellular events, but very little is known about the growth factor signaling pathways in the lens. Ras is a small GTP-binding protein downstream of growth factor receptor tyrosine kinases (RTKs) and plays a critical role in growth factor signaling. In the last grant period, we demonstrated that Ras is required for cell proliferation but not for the initiation of fiber cell differentiation during normal lens development. Other investigators have shown that signals activated by fibroblast growth factor receptors (FGFRs) are essential for fiber cell differentiation and lens cell survival. In this grant application, we will continue our investigation of the RTK-Ras signaling pathway in the lens. In Specific Aim 1 and 2, experiments are proposed to determine the role of Sprouty and ERK in lens development. Sprouty is a negative regulator of the RTK-Ras pathway and ERK is a downstream effector of Ras. In Specific Aim 3, we will explore the cell death mechanisms induced by FGFR signaling deficiency in mouse lens. The proposed experiments will provide further insights into potential ways to block lens cell proliferation and eliminate aberrant cells in the lens. Such knowledge is important for the development of methods to prevent and treat posterior capsular opacification (PCO), the most common complication of cataract surgery. Moreover, the results of this work will expand our understanding of growth factor signaling in cell proliferation and cell survival in other developmental systems and disease processes such as cancer. The purpose of this study is to investigate growth factor signaling in the developing mouse lens. This knowledge will help to develop new methods to prevent and treat posterior capsular opacification (PCO), the most common complication of cataract surgery.