Optineurin dysfunction induces neurodegeneration in normal tension glaucoma by a novel molecular mechanism

项目总结 正常眼压性青光眼以视神经病变为特征，伴有进行性视网膜神经节细胞。 (RGC)死亡和视神经(ON)退化，但在没有眼压(IOP)升高的情况下。全 目前的青光眼治疗方法是降低眼压，但对非酒精性青光眼患者效果较差。主要原因是 治疗真空是对眼压非依赖性分子机制的有限理解 青光眼变性和缺乏实用有效的NTG动物模型。基因突变的因果关系 视神经磷酸酶基因(OPTN)已在家族性和散发性NTG中发现。有趣的是，OPTN突变也 引起另一种遗传性中枢神经系统轴索病，肌萎缩侧索硬化症(ALS)，表明常见的 在脆弱的中枢神经系统神经元群体中，功能失调的OPTN可以激活退化的机制。 然而，尽管OPTN已经被广泛研究，并且它在自噬、细胞因子信号转导、 OPTN在中枢神经系统退行性变中的病理生理作用远未见报道 从Clear开始。我们最近通过截断视网膜节细胞中的OPTN基因建立了一种高效的NTG小鼠模型 具体地说，在几周内出现显著的视网膜节细胞和变性。使用这种新颖的NTG模型， 我们建议通过验证和验证OPTN突变是如何在体内导致神经变性的 视网膜神经节细胞和其他细胞中OPTN相互作用蛋白的特征。通过这些研究，我们将产生必要的 揭示与OPTN相关的青光眼神经变性的新分子机制的信息 ALS和其他中枢神经系统轴索病变也可能共享，识别RGC/ON的新修饰物 并为开发神经保护疗法提供了有价值的工具和动物模型。

PROJECT SUMMARY Normal tension glaucoma (NTG) is characterized by optic neuropathy with progressive retinal ganglion cell (RGC) death and optic nerve (ON) degeneration but in the absence of intraocular pressure (IOP) elevation. All current glaucoma treatments are to lower IOP and are less effective in NTG patients. The primary reasons for the therapeutic vacuum are the limited understanding of the molecular mechanisms of IOP-independent glaucomatous degeneration and the lack of a practical and effective NTG animal model. Causal mutations in the optineurin gene (OPTN) have been found in familial and sporadic NTG. Interestingly, OPTN mutations also cause inherited forms of another CNS axonopathy, amyotrophic lateral sclerosis (ALS), indicating a common degenerative machinery that can be activated by dysfunctional OPTN in vulnerable CNS neuronal populations. However, although OPTN has been extensively studied and its various roles in autophagy, cytokine signaling, and vesicle trafficking have been found, the pathophysiology role of OPTN in CNS neurodegeneration are far from clear. We have recently established a highly efficient NTG mouse model by truncating OPTN gene in RGCs specifically, which presents significant RGCs and ON degeneration within weeks. Using this novel NTG model, we propose to investigate how OPTN mutation causes neurodegeneration in vivo through validating and characterizing OPTN-interacting proteins in RGCs and ON. Through these studies, we will generate essential information to uncover novel molecular mechanisms of glaucomatous neurodegeneration related with OPTN that may be also shared by ALS and other CNS axonopathies, identify novel modifiers of RGC/ON neurodegeneration, and provide valuable tools and animal models to develop neuroprotection therapies.