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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Eye Institute (NEI)
Type
Research Project (R01)
Project #
5R01EY023549-05
Application #
9310254
Study Section
Biology of the Visual System Study Section (BVS)
Program Officer
Araj, Houmam H
Project Start
2013-08-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2019-07-31
Support Year
5
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Washington University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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