Mechanisms of Glucocorticoid-induced Ocular Hypertension and Glaucoma

Simple item page
dc.contributor.advisorClark, Abbot F.
dc.contributor.committeeMemberPang, Iok-Hou
dc.contributor.committeeMemberMao, Weiming
dc.creatorPatel, Gaurang C.
dc.date.accessioned2019-08-22T19:35:58Z
dc.date.available2019-08-22T19:35:58Z
dc.date.issued2017-12-01
dc.date.submitted2018-12-13T14:12:12-08:00
dc.description.abstractGlucocorticoid (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.
dc.format.mimetypeapplication/pdf
dc.identifier.urihttps://hdl.handle.net/20.500.12503/26369
dc.language.isoen
dc.provenance.legacyDownloads4
dc.subjectMedical Sciences
dc.subjectMedicine and Health Sciences
dc.subjectOcular Hypertension
dc.subjectAnimal models
dc.subjectGlucocorticoid receptor β
dc.subjectGRdim transgenic mice
dc.titleMechanisms of Glucocorticoid-induced Ocular Hypertension and Glaucoma
dc.typeDissertation
dc.type.materialtext
thesis.degree.departmentGraduate School of Biomedical Sciences
thesis.degree.grantorUniversity of North Texas Health Science Center at Fort Worth
thesis.degree.nameDoctor of Philosophy

Files

Original bundle

Now showing 1 - 1 of 1
Thumbnail Image
Name:
2017_12_gsbs_Patel_Gaurang_dissertation.pdf
Size:
144.51 MB
Format:
Adobe Portable Document Format
Download

Collections

School of Biomedical Sciences
Theses and Dissertations