Date

May 2013

Document Type

Dissertation

Degree Name

Ph.D.

Institution

Oregon Health & Science University

Abstract

Retinopathies comprise a group of non-inflammatory diseases of the retina, including diabetic retinopathy, age-related macular degeneration, and retinopathy of prematurity. These disorders impact nearly ten million people in the United States, representing the leading cause of blindness. The pathogenesis of neovascular retinopathies has been studied intensively in animal models, including a widely used mouse model of oxygen-induced retinopathy pioneered by Lois Smith.[superscript 11] Vascular endothelial growth factor, produced by Müller glia in response to hypoxia, is a potent mitogen responsible for formation of vision-destroying neovascular growths, and anti- VEGF treatments are now the standard of care for treatment of most neovascular ocular diseases. However, there remains intense interest in novel strategies for treatment of neovascular disease within academia and industry. The canonical regulatory pathway for VEGF is through Hypoxia Inducible Factor. However, more recent data from bovine aortic endothelial cells[superscript 34] revealed a novel regulator for VEGF: TEAD4, a member of the transcription enhancer factor family. Subsequent investigations at the Casey Eye Institute have shown that TEAD4 is present in primate ocular cells.[superscript 35 36] We report here that TEAD4 as well VEGF is upregulated during the neovascular phase of murine OIR. Using cell lines with Müller glia-like properties in vitro,we found that TEAD4 activates both the mouse and human VEGF promoter despite differences in critical promoter sequences. TEAD4 increased VEGF promoter activity further under hypoxia, suggesting it is involved in hypoxic induction of the gene. However, the effect appeared to be mediated indirectly through its ability to influence HIF1α transcription. Finally, immunohistochemical staining indicated that TEAD4 is expressed in endothelial cells of neovascular tufts within the OIR retina, suggesting future studies on the involvement of TEAD4 in regulation of HIF- 1 in retinal vascular endothelial cells.

Identifier

doi:10.6083/M4TQ5ZKM

Division

Neuroscience Graduate Program

School

School of Medicine

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