Targeting Soluble Epoxide Hydrolase to Treat Pathological Angiogenesis in Age-Related Macular Degeneration
Neovascular “wet” age-related macular degeneration (wet AMD) is a leading cause of blindness among the elderly, affecting millions of people worldwide. Choroidal neovascularization (CNV) is a major pathological feature of wet AMD, in which abnormal new blood-vessel growth from the choroid leads to hemorrhage, detachment of retina and irreversible loss of vision. Today, the effort to treat wet AMD is hampered by resistance and refractory responses to the current standard of anti-angiogenic care, anti-vascular endothelial growth factor therapies. Thus, there is a critical need to advance our understanding of mediators involved in CNV pathophysiology and develop novel therapeutic strategies. One such target is soluble epoxide hydrolase (sEH), which is a key enzyme that hydrolyzes epoxy fatty acids into diols in the polyunsaturated fatty acid (PUFA) metabolic pathway. This project identified sEH as a target of an antiangiogenic homoisoflavonoid, SH-11037. sEH expression and activity are upregulated in the eyes of a CNV mouse model and sEH is overexpressed in human wet AMD eyes, while pharmacological inhibition of sEH using small molecule inhibitors delivered intraocularly suppressed CNV, suggesting strong relevance of sEH in CNV. However, challenges exist because the cellular localization of sEH in the retina and how these sEH-dependent lipid molecules signal under CNV remain poorly understood. To address these questions, this project defined localization and cellular origin of sEH through immunohistochemical and RNAscope in situ hybridization analysis in human AMD and murine laser induced CNV (L-CNV) retinas. To test the hypothesis that sEH in the eye is required for CNV formation in vivo, local sEH knockdown in the retina was achieved through intraocular delivery of adeno associated virus mediated shRNA targeting Ephx2 and followed by lipid profiling and gene expression analysis. In addition, sex differences in ocular sEH expression and sex differential pharmacological response to sEH inhibitors will be examined. The effect of tissue specific knockdown of sEH on CNV, which had not been examined before, will provide additional evidence validating sEH as a key player of CNV.
I am a first-generation scientist in my family and I am a woman in science. This motivates me to pave my own path and be confident that I have the ability to inspire others through my hard work. The PhRMA Foundation’s Predoctoral Fellowship allowed me to focus solely on research to achieve my career goals and bolstered my confidence in my ability to grow as a scientist.