Ras and Phosphoinositide 3-kinase Signaling in Lens Development

描述（由申请方提供）：严格调节透镜细胞增殖、分化和存活，以实现透镜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，但对透镜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（RTK）下游的小GTP结合蛋白，并且在生长因子信号传导中起关键作用。在上一个资助期，我们证明了Ras是细胞增殖所需的，但不是在正常透镜发育过程中纤维细胞分化的起始。其他研究者已经表明，由成纤维细胞生长因子受体（FGFR）激活的信号对于纤维细胞分化和透镜细胞存活是必需的。在本基金申请中，我们将继续研究透镜中的RTK-Ras信号通路。在具体目标1和2中，提出了实验来确定Sprouty和ERK在透镜发育中的作用。Sprouty是RTK-Ras途径的负调节因子，ERK是Ras的下游效应因子。在具体目标3中，我们将探讨小鼠透镜中FGFR信号转导缺陷诱导的细胞死亡机制。提出的实验将提供进一步的见解，以潜在的方式来阻止透镜细胞增殖和消除异常细胞的透镜。这些知识对于预防和治疗后囊混浊（PCO）（白内障手术最常见的并发症）的方法的发展非常重要。此外，这项工作的结果将扩大我们对细胞增殖和细胞存活中生长因子信号传导在其他发育系统和疾病过程（如癌症）中的理解。本研究的目的是探讨生长因子信号在发育中的小鼠透镜。这些知识将有助于开发新的方法来预防和治疗后囊混浊（PCO），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.