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

项目摘要 正常眼压性青光眼（Normal tension glaucoma，NTG）是一种以视网膜神经节细胞进展为特征的视神经病变 (RGC)死亡和视神经（ON）变性，但没有眼内压（IOP）升高。所有 目前的青光眼治疗是降低IOP，并且在NTG患者中效果较差。的主要原因 治疗真空是对IOP非依赖性的分子机制的有限理解 目前还缺乏实用有效的NTG动物模型。基因突变 在家族性和散发性NTG中发现了视神经磷酸酶基因（optineurin，OPTN）。有趣的是，OPTN突变也 引起另一种CNS轴突病的遗传形式，肌萎缩侧索硬化症（ALS），表明一种常见的 在脆弱的CNS神经元群体中，可以通过功能失调的OPTN激活退行性机制。 然而，尽管OPTN已经被广泛研究，并且其在自噬、细胞因子信号传导、 和囊泡运输的发现，OPTN在中枢神经系统退行性变中的病理生理作用还远未阐明 从Clear我们最近建立了一个高效的NTG小鼠模型，通过截断RGC中的OPTN基因 具体地，其在数周内呈现显著的RGC和ON变性。使用这种新的NTG模型， 我们建议通过验证和研究OPTN突变如何导致体内神经退行性变， 通过这些研究，我们将产生重要的 揭示与OPTN相关的脑昏迷性神经变性的新分子机制的信息， 也可能是ALS和其他CNS轴突病共有的，鉴定RGC/ON的新修饰剂 神经退行性变，并为开发神经保护疗法提供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.