EPH-RECEPTOR SIGNALING IN LENS DEVELOPMENT AND AGING

项目摘要 EPH-受体酪氨酸激酶激活参与多种生物学和免疫调节的复杂信号网络， 病理过程包括胚胎发育、组织再生、免疫监视、肿瘤 进展和病毒感染。最近，编码这些受体之一EPHA 2的基因的变异， 与遗传性和年龄相关的人类白内障有关，EPHA 2已被鉴定为一种 透镜膜蛋白质组的丰富但知之甚少的组分。这个项目的总体目标是 研究的目的是促进对透镜发育和老化中的EPH受体信号传导的理解。在这 建议我们将进行跨学科的方法，以阐明分子机制，连接遗传 具有透镜表型的EPHA 2变异。首先，我们将进行靶向测序，以确定 EPHA 2编码变异与透镜老化的关系。其次，我们将使用基因靶向小鼠， 成像技术来表征透镜发育过程中的EPHA 2功能和功能障碍。最后我们将 采用蛋白质组学技术来表征透镜中的EPHA 2信号传导和加工。结果 这些研究将提供关于在透镜发育中EPH受体信号传导作用的新见解， 衰老，在白内障形成的背景下-视力障碍的重要原因。

Project Summary EPH-receptor tyrosine kinases activate complex signaling networks involved in diverse biological and pathological processes including embryonic development, tissue regeneration, immune surveillance, tumor progression and viral infection. Recently, variations in the gene encoding one of these receptors, EPHA2, have been associated with inherited and age-related forms of human cataract, and EPHA2 has been identified as an abundant, but poorly understood, component of the lens membrane proteome. The overall goal of this research is to advance understanding of EPH-receptor signaling in lens development and aging. In this proposal we will conduct an interdisciplinary approach to elucidate molecular mechanisms that connect genetic variation in EPHA2 with lens phenotype. First, we will perform targeted-sequencing to determine the relationship between EPHA2 coding variation and lens aging. Second, we will use gene-targeted mice and imaging techniques to characterize EPHA2 function and dysfunction during lens development. Finally we will undertake proteomics techniques to characterize EPHA2 signaling and processing in the lens. Results from these studies will provide new insights regarding the role of EPH-receptor signaling in lens development and aging, within the context of cataract formation - an important cause of visual impairment.