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.
This research seeks to elucidate molecular genetics mechanisms involved in development and aging of the ocular lens, and to advance understanding of cataract formation - a universally important cause of low vision and blindness.
| Zhou, Yuefang; Shiels, Alan (2018) Epha2 and Efna5 participate in lens cell pattern-formation. Differentiation 102:1-9 |
| Shiels, Alan; Hejtmancik, J Fielding (2017) Mutations and mechanisms in congenital and age-related cataracts. Exp Eye Res 156:95-102 |
| Bennett, Thomas M; M'Hamdi, Oussama; Hejtmancik, J Fielding et al. (2017) Germ-line and somatic EPHA2 coding variants in lens aging and cataract. PLoS One 12:e0189881 |
| Bennett, Thomas M; Zhou, Yuefang; Shiels, Alan (2016) Lens transcriptome profile during cataract development in Mip-null mice. Biochem Biophys Res Commun 478:988-93 |
| Zhou, Yuefang; Bennett, Thomas M; Shiels, Alan (2016) Lens ER-stress response during cataract development in Mip-mutant mice. Biochim Biophys Acta 1862:1433-42 |
