Mutant human myocilin induces strain specific differences in ocular hypertension and optic nerve damage in mice.
Mutant human myocilin induces strain specific differences in ocular hypertension and optic nerve damage in mice.
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DOI：
10.1016/j.exer.2012.04.016
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发表时间：
2012-07
影响因子：
3.4
通讯作者：
Clark, Abbot F.
中科院分区：
文献类型：
--
作者：
McDowell, Colleen M.;Luan, Tomi;Zhang, Zhang;Putliwala, Tasneem;Wordinger, Robert J.;Millar, J. Cameron;John, Simon W. M.;Pang, Iok-Hou;Clark, Abbot F.
眼内压升高（IOP）是青光眼发生和进展的危险因素。肌纤蛋白 (MYOC) 的青光眼突变会损害小梁网并导致人类和小鼠的眼压升高。青光眼动物模型对于发现和更好地理解分子致病途径以及测试新的青光眼疗法非常重要。尽管已经开发并表征了许多不同的青光眼动物模型，但还没有真正的人类原发性开角型青光眼（POAG）模型。这项工作的总体目标是开发第一个可诱导的 POAG 小鼠模型，利用人类 POAG 相关转基因（即突变型 MYOC）在小鼠眼中的表达来提高眼压并引起视神经压力诱导损伤。本研究使用了四种小鼠品系（A/J、BALB/cJ、C57BL/6J 和 C3H/HeJ）。将 Ad5.MYOC.Y437H (5 × 107 pfu) 玻璃体内注射到一只眼睛中，未注射的对侧眼睛作为对照眼。使用 TonoLab 回弹眼压计进行有意识的 IOP 测量。通过对 PPD 染色的视神经横截面进行评分来确定视神经损伤。通过尼氏染色细胞计数评估视网膜神经节细胞和上丘损伤。玻璃体内注射病毒载体 Ad5.MYOC.Y437H 导致 BALB/cJ、A/J 和 C57BL/6J 小鼠出现长期、可重复且具有统计学意义的 IOP 升高。 IOP 在 8 周内增加至约 25 mm Hg (p<0.0001)。相比之下，C3H/HeJ 小鼠品系在 8 周时间内对 Ad5.MYOC.Y437H 诱导的 IOP 升高具有抵抗力。未注射的对照眼的眼压稳定（12-15 mm Hg）。我们还确定了压力引起的视神经损伤是否存在任何应变差异。尽管三个测试品系（BALB/cJ、C57BL/6J 和 A/J）的 IOP 类似地升高，但只有 A/J 品系在 8 周结束时出现相当大且显着的视神经损伤，注射眼中视神经损伤评分为 2.64 +/- 0.19（n=18，p<0.001）。在任何测试的菌株中，8周时间点的视网膜神经节细胞死亡或上丘损伤没有统计学差异。这些结果证明对 Ad5.MYOC.Y437H 诱导的高眼压和压力诱导的视神经损伤的应变依赖性反应。
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 × 107 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.
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