Browsing by Subject "Ocular Hypertension"
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Item Mechanisms of Glucocorticoid-induced Ocular Hypertension and Glaucoma(2017-12-01) Patel, Gaurang C.; Clark, Abbot F.; Pang, Iok-Hou; Mao, WeimingGlucocorticoid (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.Item Proteomics-Based Identification of Retinal Protein Networks Impacted by Elevated Intraocular Pressure in the Hypertonic Saline Injection Model of Experimental Glaucoma(MDPI, 2023-08-26) Zaman, Khadiza; Nguyen, Vien; Prokai-Tatrai, Katalin; Prokai, LaszloElevated intraocular pressure is considered a major cause of glaucomatous retinal neurodegeneration. To facilitate a better understanding of the underlying molecular processes and mechanisms, we report a study focusing on alterations of the retina proteome by induced ocular hypertension in a rat model of the disease. Glaucomatous processes were modeled through sclerosing the aqueous outflow routes of the eyes by hypertonic saline injections into an episcleral vein. Mass spectrometry-based quantitative retina proteomics using a label-free shotgun methodology identified over 200 proteins significantly affected by ocular hypertension. Various facets of glaucomatous pathophysiology were revealed through the organization of the findings into protein interaction networks and by pathway analyses. Concentrating on retinal neurodegeneration as a characteristic process of the disease, elevated intraocular pressure-induced alterations in the expression of selected proteins were verified by targeted proteomics based on nanoflow liquid chromatography coupled with nano-electrospray ionization tandem mass spectrometry using the parallel reaction monitoring method of data acquisition. Acquired raw data are shared through deposition to the ProteomeXchange Consortium (PXD042729), making a retina proteomics dataset on the selected animal model of glaucoma available for the first time.Item The regulation of transforming growth factor beta-2-induced ocular hypertension and glaucomatous environment in the trabecular meshwork(2020-12) Roberts, Amanda L.; Clark, Abbot F.; Krishnamoorthy, Raghu R.; Pang, Iok-Hou; Tovar-Vidales, Tara; Gatch, Michael B.Glaucoma is a heterogeneous group of optic neuropathies that damage the optic nerve that leads to progressive visual loss and irreversible blindness in over 80 million people worldwide. Primary open angle glaucoma (POAG) is the most common form of glaucoma, and elevated intraocular pressure (IOP) is the major risk factor for the development and progression of this ocular disease. One of the potential mechanisms responsible for elevated IOP in POAG patients is the excessive accumulation of extracellular matrix (ECM) proteins within the trabecular meshwork (TM). Damage to the TM impairs the aqueous humor outflow and increases aqueous humor outflow resistance, and elevates IOP. Discovering potential new disease modifying targets to lower IOP is necessary to develop effective therapies to inhibit the progression of glaucoma. Here, we explored a novel molecular mechanism involved in the development of glaucomatous TM ECM damage. The effects of transforming growth factor beta 2 (TGF[beta]2) signaling pathways in the TM ECM have been extensively studied. TGF[beta]2 is a profibrotic signaling component in ocular hypertension development that increases ECM deposition in the TM. As a member of the toll-like receptor family, toll-like receptor 4 (TLR4) was originally identified as the receptor for lipopolysaccharide (LPS). TLR4 can also be activated by endogenous ligands known as damaged associated molecular patterns (DAMPS), which are generated as a result of injury, cell damage, and ECM remodeling. DAMP-induced TLR4 activation has been linked to fibrosis, ECM protein deposition, and augmented TGF[beta]2 signaling and downstream fibrotic responses. Recently, we identified TGF[beta]2-TLR4 signaling crosstalk that regulates the TM ECM, and mutation in TLR4 rescues TGF[beta]2-induced ocular hypertension in mice. The goal of this work was to investigate the role of the endogenous TLR4 ligand fibronectin containing extra domain A isoform (FN-EDA), and the TLR4 downstream signaling molecule NF[kappa]B in TGF[beta]2-induced ocular hypertension in mice. Overall, we discovered that TLR4, FNEDA and NF[kappa]B are necessary for TGF[beta]2-induced ocular hypertension and ECM deposition in mice. In addition, constitutively active EDA mice spontaneously develop ocular hypertension. These data provide new targets to lower IOP and inhibit glaucoma disease progression.