Browsing by Subject "Glaucoma / genetics"
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Item Glucocorticoid Receptor Transactivation Is Required for Glucocorticoid-Induced Ocular Hypertension and Glaucoma(ARVO Journals, 2019-05) Patel, Gaurang C.; Millar, J. Cameron; Clark, Abbot F.Purpose: Glucocorticoid (GC)-induced ocular hypertension (GC-OHT) is a serious side effect of prolonged GC therapy that can lead to glaucoma and permanent vision loss. GCs cause a plethora of changes in the trabecular meshwork (TM), an ocular tissue that regulates intraocular pressure (IOP). GCs act through the glucocorticoid receptor (GR), and the GR regulates transcription both through transactivation and transrepression. Many of the anti-inflammatory properties of GCs are mediated by GR transrepression, while GR transactivation largely accounts for GC metabolic effects and side effects of GC therapy. There is no evidence showing which of the two mechanisms plays a role in GC-OHT. Methods: GRdim transgenic mice (which have active transrepression and impaired transactivation) and wild-type (WT) C57BL/6J mice received weekly periocular dexamethasone acetate (DEX-Ac) injections. IOP, outflow facilities, and biochemical changes to the TM were determined. Results: GRdim mice did not develop GC-OHT after continued DEX treatment, while WT mice had significantly increased IOP and decreased outflow facilities. Both TM tissue in eyes of DEX-treated GRdim mice and cultured TM cells isolated from GRdim mice had reduced or no change in the expression of fibronectin, myocilin, collagen type I, and alpha-smooth muscle actin (alpha-SMA). GRdim mouse TM (MTM) cells also had a significant reduction in DEX-induced cytoskeletal changes, which was clearly seen in WT MTM cells. Conclusions: We provide the first evidence for the role of GR transactivation in regulating GC-mediated gene expression in the TM and in the development of GC-OHT. This discovery suggests a novel therapeutic approach for treating ocular inflammation without causing GC-OHT and glaucoma.Item Mirna Expression in Glaucomatous and TGFbeta2 Treated Lamina Cribrosa Cells(MDPI, 2021-06-08) Lopez, Navita N.; Rangan, Rajiv; Clark, Abbot F.; Tovar-Vidales, TaraGlaucoma is a group of optic neuropathies that leads to irreversible vision loss. The optic nerve head (ONH) is the site of initial optic nerve damage in glaucoma. ONH-derived lamina cribrosa (LC) cells synthesize extracellular matrix (ECM) proteins; however, these cells are adversely affected in glaucoma and cause detrimental changes to the ONH. LC cells respond to mechanical strain by increasing the profibrotic cytokine transforming growth factor-beta 2 (TGFbeta2) and ECM proteins. Moreover, microRNAs (miRNAs or miR) regulate ECM gene expression in different fibrotic diseases, including glaucoma. A delicate homeostatic balance between profibrotic and anti-fibrotic miRNAs may contribute to the remodeling of ONH. This study aimed to determine whether modulation of miRNAs alters the expression of ECM in human LC cells. Primary human normal and glaucoma LC cells were grown to confluency and treated with or without TGFbeta2 for 24 h. Differences in expression of miRNAs were analyzed using miRNA qPCR arrays. miRNA PCR arrays showed that the miR-29 family was significantly decreased in glaucomatous LC cell strains compared to age-matched controls. TGFbeta2 treatment downregulated the expression of multiple miRNAs, including miR-29c-3p, compared to controls in LC cells. LC cells transfected with miR-29c-3p mimics or inhibitors modulated collagen expression.Item Sigma-1R Protects Retinal Ganglion Cells in Optic Nerve Crush Model for Glaucoma(ARVO Journals, 2021-08-18) Li, Linya; He, Shaoqing; Liu, Yang; Yorio, Thomas; Ellis, Dorette Z.Purpose: The purpose of this study was to determine the effects of the Sigma-1R (sigma-1r) on retinal ganglion cell (RGC) survival following optic nerve crush (ONC) and the signaling mechanism involved in the sigma-1r protection. Methods: The overall strategy was to induce injury by ONC and mitigate RGC death by increasing sigma-1r expression and/or activate sigma-1r activity in sigma-1r K/O mice and wild type (WT) mice. AAV2-sigma-1r vector was used to increase sigma-1r expression and sigma-1r agonist used to activate the sigma-1r and RGCs were counted. Immunohistochemical and Western blot analysis determined phosphorylated (p)-c-Jun, c-Jun, and Caspase-3. Pattern electroretinography (PERG) determined RGC activity. Results: RGC counts and function were similar in pentazocine-treated WT mice when compared to untreated mice and in WT mice when compared with sigma-1r K/O mice. Pentazocine-induced effects and the effects of sigma-1r K/O were only observable after ONC. ONC resulted in decreased RGC counts and activity in both WT and sigma-1r K/O mice, with sigma-1r K/O mice experiencing significant decreases compared with WT mice. The sigma-1r transgenic expression resulted in increased RGC counts and activity following ONC. In WT mice, treatment with sigma-1r agonist pentazocine resulted in increased RGC counts and increased activity when compared with untreated WT mice. There were time-dependent increases in c-jun, p-c-jun, and caspase-3 expression in ONC mice that were mitigated with pentazocine-treatment. Conclusions: These findings suggest that the apoptotic pathway is involved in RGC losses seen in an ONC model. The sigma-1r offers neuroprotection, as activation and/or transgenic expression of sigma-1r attenuated the apoptotic pathway and restored RGCs number and function following ONC.