Assessment of optic neuropathy as a result of direct and indirect injury using non- invasive functional and structural analytical tools

Optic neuropathy, as a result of various factors, is a leading cause of blindness in the world. The early diagnosis of optic nerve damage can aid therapeutic intervention, and experimental studies characterizing relevant diagnostic tools in different optic neuropathy models are currently lacking. In order to address this gap in current scientific literature, we aim to validate the following overarching hypothesis in this dissertation. The progression of optic neuropathy as a result of direct and indirect injury to the optic nerve can be reliably assessed using non-invasive functional and structural analytical tools. In order to verify this hypothesis, we have conceived and implemented the following specific aims. Specific Aim I: To characterize optic nerve structure and function using non-invasive tools in healthy C57/bl6 mice. Specific Aim II: To evaluate optic nerve status in C57/bl6 mice with experimentally induced Parkinson\u27s disease, as a model of indirect injury to the optic nerve. Specific Aim III: To evaluate optic nerve status in C57/bl6 mice following blast injury, as a model of direct injury to the optic nerve

Imaging Data on Characterization of Retinal Autofluorescent Lesions in a Mouse Model of Juvenile Neuronal Ceroid Lipofuscinosis (CLN3 Disease)

Juvenile neuronal ceroid lipofuscinosis (JNCL, aka. juvenile Batten disease or CLN3 disease), a lethal pediatric neurodegenerative disease without cure, often presents with vision impairment and characteristic ophthalmoscopic features including focal areas of hyper-autofluorescence. In the associated research article “Loss of CLN3, the gene mutated in juvenile neuronal ceroid lipofuscinosis, leads to metabolic impairment and autophagy induction in retinal pigment epithelium” (Zhong et al., 2020) [1], we reported ophthalmoscopic observations of focal autofluorescent lesions or puncta in the Cln3Δex7/8 mouse retina at as young as 8 month old. In this data article, we performed differential interference contrast and confocal imaging analyses in all retinal layers to localize and characterize these autofluorescent lesions, including their spectral characteristics and morphology. We further studied colocalization of these autofluorescent lesions with the JNCL marker mitochondrial ATP synthase F0 sub-complex subunit C and various established retinal cell type markers

Topical ocular sodium 4-phenylbutyrate rescues glaucoma in a myocilin mouse model of primary open-angle glaucoma

PURPOSE. Mutations in the myocilin gene (MYOC) are the most common known genetic cause of primary open-angle glaucoma (POAG). The purpose of this study was to determine whether topical ocular sodium 4-phenylbutyrate (PBA) treatment rescues glaucoma phenotypes in a mouse model of myocilin-associated glaucoma (Tg-MYOC Y437H mice). METHODS. Tg-MYOC Y437H mice were treated with PBA eye drops (n ϭ 10) or sterile PBS (n ϭ 8) twice daily for 5 months. Long-term safety and effectiveness of topical PBA (0.2%) on glaucoma phenotypes were examined by measuring intraocular pressure (IOP) and pattern ERG (PERG), performing slit lamp evaluation of the anterior chamber, analyzing histologic sections of the anterior segment, and comparing myocilin levels in the aqueous humor and trabecular meshwork of Tg-MYOC Y437H mice. Sci. 2012;53: 1557-1565 RESULTS. Tg-MYO

Assessment of optic neuropathy as a result of direct and indirect injury using non- invasive functional and structural analytical tools

Optic neuropathy, as a result of various factors, is a leading cause of blindness in the world. The early diagnosis of optic nerve damage can aid therapeutic intervention, and experimental studies characterizing relevant diagnostic tools in different optic neuropathy models are currently lacking. In order to address this gap in current scientific literature, we aim to validate the following overarching hypothesis in this dissertation. The progression of optic neuropathy as a result of direct and indirect injury to the optic nerve can be reliably assessed using non-invasive functional and structural analytical tools. In order to verify this hypothesis, we have conceived and implemented the following specific aims. Specific Aim I: To characterize optic nerve structure and function using non-invasive tools in healthy C57/bl6 mice. Specific Aim II: To evaluate optic nerve status in C57/bl6 mice with experimentally induced Parkinson's disease, as a model of indirect injury to the optic nerve. Specific Aim III: To evaluate optic nerve status in C57/bl6 mice following blast injury, as a model of direct injury to the optic nerve.</p

Characterization of structure and function of the mouse retina using pattern electroretinography, pupil light reflex, and optical coherence tomography

Objective  To perform in vivo analysis of retinal functional and structural parameters in healthy mouse eyes. Animal Studied  Adult C57BL/6 male mice (n = 37). Procedures  Retinal function was evaluated using pattern electroretinography (pERG) and the chromatic pupil light reflex (cPLR). Structural properties of the retina and nerve fiber layer (NFL) were evaluated using spectral-domain optical coherence tomography (SD-OCT). Results  The average pERG amplitudes were found to be 11.2 ± 0.7 μV (P50-N95, mean ± SEM), with an implicit time for P50-N95 interval of 90.4 ± 5.4 ms. Total retinal thickness was 229.5 ± 1.7 μm (mean ± SEM) in the area centralis region. The thickness of the retinal nerve fiber layer (mean ± SEM) using a circular peripapillary retinal scan centered on the optic nerve was 46.7 ± 0.9 μm (temporal), 46.1 ± 0.9 μm (superior), 45.8 ± 0.9 μm (nasal), and 48.4 ± 1 μm (inferior). The baseline pupil diameter was 2.1 ± 0.05 mm in darkness, and 1.1 ± 0.05 and 0.56 ± 0.03 mm after stimulation with red (630 nm, luminance 200 kcd/m2) or blue (480 nm, luminance 200 kcd/m2) light illumination, respectively. Conclusions  Pattern electroretinography, cPLR and SD-OCT analysis are reproducible techniques, which can provide important information about retinal and optic nerve function and structure in mice.This article is from Veterinary Ophthalmology 15 (2012): 94, doi: 10.1111/j.1463-5224.2012.01034.x.</p

Reduction of ER stress via a chemical chaperone prevents disease phenotypes in a mouse model of primary open angle glaucoma

Mutations in myocilin (MYOC) are the most common genetic cause of primary open angle glaucoma (POAG), but the mechanisms underlying MYOC-associated glaucoma are not fully understood. Here, we report the development of a transgenic mouse model of POAG caused by the Y437H MYOC mutation; the mice are referred to herein as Tg-MYOCY437H mice. Analysis of adult Tg-MYOCY437H mice, which we showed express human MYOC containing the Y437H mutation within relevant eye tissues, revealed that they display glaucoma phenotypes (i.e., elevated intraocular pressure [IOP], retinal ganglion cell death, and axonal degeneration) closely resembling those seen in patients with POAG caused by the Y437H MYOC mutation. Mutant myocilin was not secreted into the aqueous humor but accumulated in the ER of the trabecular meshwork (TM), thereby inducing ER stress in the TM of Tg-MYOCY437H mice. Furthermore, chronic and persistent ER stress was found to be associated with TM cell death and elevation of IOP in Tg-MYOCY437H mice. Reduction of ER stress with a chemical chaperone, phenylbutyric acid (PBA), prevented glaucoma phenotypes in Tg-MYOCY437H mice by promoting the secretion of mutant myocilin in the aqueous humor and by decreasing intracellular accumulation of myocilin in the ER, thus preventing TM cell death. These results demonstrate that ER stress is linked to the pathogenesis of POAG and may be a target for treatment in human patients