EPH-RECEPTOR SIGNALING IN LENS DEVELOPMENT AND AGING

描述（由申请人提供）：epf受体酪氨酸激酶激活复杂的信号网络，涉及多种生物和病理过程，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EPHA2的基因变异与遗传性和年龄相关的人类白内障有关，EPHA2已被确定为晶状体膜蛋白质组的丰富成分，但对其知之甚少。本研究的总体目标是促进对晶状体发育和衰老过程中ef受体信号传导的理解。在本提案中，我们将采用跨学科的方法来阐明EPHA2遗传变异与晶状体表型之间的分子机制。首先，我们将进行靶向测序，确定EPHA2编码变异与晶状体老化之间的关系。其次，我们将使用基因靶向小鼠和成像技术来表征晶状体发育过程中EPHA2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EPHA2在晶状体中的信号传导和加工。这些研究结果将为在白内障形成的背景下，eph受体信号在晶状体发育和衰老中的作用提供新的见解-白内障是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.