Date of Award

12-1-2017

Degree Type

Dissertation

Degree Name

Doctor of Philosophy

Department

Graduate School of Biomedical Sciences

First Advisor

Abbot F. Clark

Second Advisor

Iok-Hou Pang

Third Advisor

Weiming Mao

Abstract

Glucocorticoid (GC)-induced ocular hypertension (OHT) is a serious side-effect of prolonged GC therapy that can lead to iatrogenic glaucoma and permanent vision loss. Patients with GCOHT have open iridocorneal angles and increased outflow resistance in the trabecular meshwork (TM) outflow pathway, similar to that seen in POAG. However, the molecular mechanisms responsible for GC-induced OHT are not entirely clear. GCs acts through glucocorticoid receptor (GR), and GR can regulate transcription both through transactivation and transrepression mechanisms. However, there is no evidence showing which of the two mechanisms play role in GC-induced OHT. In addition, the alternatively spliced isoform of glucocorticoid receptor GRβ acts as dominant negative regulator of GC activity, and it has been shown that overexpressing GRβ in TM cells inhibits GC-induced glaucomatous damage in TM cells. Therefore, we hypothesized that GR transactivation through the GRα isoform elevates IOP and that overexpression of GRβ decreases IOP upon GC treatment. We developed a mouse model that mimics many aspects of GC-OHT in humans to help us understand precise molecular mechanisms and etiology of GC-OHT, and we further demonstrated that myocilin does not play a major role in DEX-induced OHT in mice. We also provide the first evidence of the in vivo physiological role of GRβ in regulating GC-OHT and GC-mediated gene expression in the TM. Furthermore, we use GRdim transgenic mice (which have active transrepression and impaired transactivation) to determine the GR functions that regulate GC-OHT and provide first evidence of the role of GR transactivation in regulating GC-mediated gene expression in the TM and GC-OHT in mice. These studies all combine will significantly advance our knowledge in designing useful therapeutic approaches for GC-induced OHT and glaucoma.

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