Molecular Mechanisms Of Glaucoma

青光眼的分子机制

• 批准号: 7594062
• 负责人: Stanislav I Tomarev
• 金额: $ 181.73万
• 依托单位: NATIONAL EYE INSTITUTE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7594062
• 关键词: Actins; Animal Genetics; Aqueous Humor; C-terminal; Cells; Cultured Cells; Cytoskeleton; Data; Development; Eye; Family; Genes; Genetic; Glaucoma; Goals; Lead; Modeling; Molecular; Mutation; Patients; Physiologic Intraocular Pressure; Primary Open Angle Glaucoma; Property; Proteins; Regulation; Signal Pathway; Signal Transduction; System; Trabecular meshwork structure; Wnt proteins; interest; myocilin; novel strategies; olfactomedin

It is now well established that a genetic component may contribute to glaucoma, and several glaucoma-associated genes have been identified. The first identified and the most studied gene is Myocilin, which is heavily expressed in and secreted by the trabecular meshwork, one of the key components of the eye aqueous humor outflow system. The myocilin protein belongs to a family of glycosylated proteins containing a C-terminal olfactomedin domain. Dominant mutations in Myocilin are found in 3-4% of patients with primary open angle glaucoma and most of these glaucoma-causing mutations are located in the olfactomedin domain. The function of wild-type Myocilin is not clear. We continue to study function of myocilin and two related olfactomedin domain-containing proteins, olfactomedin 1 and optimedin. We demonstrated that these three proteins are able to induce changes in cell actin cytoskeleton similar to those induced by wnt proteins. Subsequent analysis indicated that olfactomedin 1 and myocilin may serve as modulators of the non-canonical wnt-signaling pathway and interact with several key component of wnt-signaling pathway including Wif1 and sFRP1. These data add Myocilin and olfactomedin 1 to the list of the proteins involved in wnt signaling. We suggest that Myocilin is involved in the regulation of intraocular pressure through alteration of contractility of the trabecular meshwork.

现在已经很好地确定，遗传成分可能有助于青光眼，并且已经鉴定出了几种与青光眼相关的基因。第一个鉴定出和研究最多的基因是肌动蛋白，该基因在小梁网中大量表达并分泌，这是眼睛水性幽默流出系统的关键组成部分之一。肌动蛋白蛋白属于含有C-末端嗅觉蛋白结构域的糖基化蛋白家族。在3-4％的原发性开角青光眼患者中发现了肌动蛋白的显性突变，这些引起青光眼的突变大多数位于橄榄毒素结构域中。野生型肌动蛋白的功能尚不清楚。我们继续研究肌动蛋白和两种相关的含橄榄蛋白结构蛋白蛋白的功能，即橄榄毒素1和优化素。我们证明，这三种蛋白能够诱导与Wnt蛋白诱导的细胞肌动蛋白细胞骨架的变化。随后的分析表明，嗅觉素1和肌动蛋白可以用作非经典WNT信号途径的调节剂，并与包括WIF1和SFRP1在内的Wnt信号途径的多个关键组成部分相互作用。这些数据将肌动蛋白和嗅觉素1添加到与Wnt信号传导有关的蛋白质列表中。我们建议肌动蛋白通过改变小梁网的收缩力来调节眼内压。