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

Optineurin功能障碍通过一种新的分子机制诱导正常眼压青光眼的神经变性

基本信息

批准号：
10557146
负责人：
Yang Hu
金额：
$ 54.57万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557146
关键词：
Amyotrophic Lateral Sclerosis Animal Model Autophagocytosis Axon Axonal Transport Biochemical Biological Assay Biotin Blindness Cell Death Collaborations Cytokine Signaling Data Environment Failure Functional disorder Gene Mutation Genes Glaucoma Goals Histologic Human Hybrids Image Impairment Inherited Intervention Link Mediating Mitochondria Modeling Molecular Monitor Morphology Mus Mutation Nerve Degeneration Neurons Ocular Hypertension Optic Nerve Pathogenesis Pathogenicity Pathway interactions Patients Phenotype Physiologic Intraocular Pressure Play Population Positioning Attribute Proteins Retina Retinal Ganglion Cells Role Scientist Structure Testing Therapeutic Time Transgenic Mice Vacuum Vesicle Yeasts axonal degeneration axonopathy cDNA Library causal variant experimental study gene function gene interaction in vivo mouse model mutant neural repair neuronal survival neuroprotection new therapeutic target novel optic nerve disorder overexpression receptor syntaphilin tool trafficking

项目摘要

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.

项目摘要正常的张力青光眼（NTG）的特征是与进行性视网膜神经节细胞的视神经病变（RGC）死亡和视神经（ON）变性，但在没有眼内压（IOP）升高的情况下。全部当前的青光眼治疗降低IOP，在NTG患者中效果较低。主要原因治疗真空是对IOP独立的分子机制的有限理解青光眼变性以及缺乏实用有效的NTG动物模型。因果突变在家族性和零星NTG中发现了Optineurin基因（OPTN）。有趣的是，OPTN突变原因是另一种CNS轴突病的遗传形式，肌萎缩性侧向硬化症（ALS），表明一个常见脆弱的CNS神经元种群中功能失调的OPTN可以激活的退化机制。然而，尽管已经对OPTN进行了广泛的研究及其在自噬，细胞因子信号传导中的各种作用，但已经发现了囊泡运输，OPTN在CNS神经变性中的病理生理作用远从清晰。我们最近通过在RGC中截断OPTN基因建立了高效的NTG小鼠模型具体而言，它在几周内提出了重要的RGC和变性。使用这种新颖的NTG模型，我们建议通过验证和表征RGC和ON中的OPTN相互作用蛋白。通过这些研究，我们将产生重要信息以发现与Optn相关的青光眼神经变性的新型分子机制 ALS和其他CNS轴突病也可以共享，识别RGC/ON的新型修饰符神经变性，并提供有价值的工具和动物模型来开发神经保护疗法。