Mutant human myocilin induces strain specific differences in ocular hypertension and optic nerve damage in mice
| Autor: | Abbot F. Clark, Tomi Luan, Tasneem Putliwala, Iok-Hou Pang, Robert J. Wordinger, Colleen M McDowell, J. Cameron Millar, Simon W. M. John, Zhang Zhang |
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| Rok vydání: | 2012 |
| Předmět: |
Intraocular pressure
medicine.medical_specialty genetic structures Mice Inbred A Genetic Vectors Ocular hypertension Glaucoma Biology Article Adenoviridae Immunoenzyme Techniques Mice Tonometry Ocular Cellular and Molecular Neuroscience Species Specificity Ophthalmology Optic Nerve Diseases medicine Animals Transgenes Eye Proteins Intraocular Pressure Myocilin Glycoproteins Mice Inbred BALB C Mice Inbred C3H Intravitreal administration Anatomy medicine.disease eye diseases Sensory Systems Mice Inbred C57BL Cytoskeletal Proteins Disease Models Animal medicine.anatomical_structure Retinal ganglion cell Intravitreal Injections Optic nerve Female Ocular Hypertension sense organs Trabecular meshwork Glaucoma Open-Angle |
| Zdroj: | Experimental Eye Research. 100:65-72 |
| ISSN: | 0014-4835 |
| DOI: | 10.1016/j.exer.2012.04.016 |
| Popis: | Elevated intraocular pressure (IOP) is a causative risk factor for the development and progression of glaucoma. Glaucomatous mutations in myocilin (MYOC) damage the trabecular meshwork and elevate IOP in humans and in mice. Animal models of glaucoma are important to discover and better understand molecular pathogenic pathways and to test new glaucoma therapeutics. Although a number of different animal models of glaucoma have been developed and characterized, there are no true models of human primary open angle glaucoma (POAG). The overall goal of this work is to develop the first inducible mouse model of POAG using a human POAG relevant transgene (i.e. mutant MYOC) expression in mouse eyes to elevate IOP and cause pressure-induced damage to the optic nerve. Four mouse strains (A/J, BALB/cJ, C57BL/6J, and C3H/HeJ) were used in this study. Ad5.MYOC.Y437H (5 × 10(7) pfu) was injected intravitreally into one eye, with the uninjected contralateral eye serving as the control eye. Conscious IOP measurements were taken using a TonoLab rebound tonometer. Optic nerve damage was determined by scoring PPD stained optic nerve cross sections. Retinal ganglion cell and superior colliculus damage was assessed by Nissl stain cell counts. Intravitreal administration of viral vector Ad5.MYOC.Y437H caused a prolonged, reproducible, and statistically significant IOP elevation in BALB/cJ, A/J, and C57BL/6J mice. IOPs increased to approximately 25 mm Hg for 8 weeks (p < 0.0001). In contrast, the C3H/HeJ mouse strain was resistant to Ad5.MYOC.Y437H induced IOP elevation for the 8-week time period. IOPs were stable (12-15 mm Hg) in the uninjected control eyes. We also determined whether there were any strain differences in pressure-induced optic nerve damage. Even though IOP was similarly elevated in three of the strains tested (BALB/cJ, C57BL/6J, and A/J) only the A/J strain had considerable and significant optic nerve damage at the end of 8 weeks with optic nerve damage score of 2.64 ± 0.19 (n = 18, p < 0.001) in the injected eye. There was no statistical difference in retinal ganglion cell death or superior colliculus damage at the 8-week time point in any of the strains tested. These results demonstrate strain dependent responses to Ad5.MYOC.Y437H-induced ocular hypertension and pressure-induced optic nerve damage. |
| Databáze: | OpenAIRE |
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