EPH-RECEPTOR SIGNALING IN LENS DEVELOPMENT AND AGING

描述（由申请人提供）：EPH受体酪氨酸激酶激活复杂的信号传导网络，这些信号传导网络参与多种生物学和病理学过程，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形式的人类白内障相关，并且EPHA 2已被鉴定为透镜膜蛋白质组的丰富但知之甚少的组分。本研究的总体目标是促进对透镜发育和衰老中的EPH受体信号传导的理解。在这个建议中，我们将进行一个跨学科的方法来阐明连接EPHA 2的遗传变异与透镜表型的分子机制。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之间的关系。其次，我们将使用基因靶向小鼠和成像技术来表征透镜发育过程中EPHA 2的功能和功能障碍。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。这些研究的结果将提供新的见解，在白内障形成的背景下，在透镜发育和衰老中的作用，EPH受体信号传导-视力障碍的重要原因。

DESCRIPTION (provided by applicant): 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.