Neuroprotection by Modulating ER Stress in Glaucoma

通过调节 ER 应激对青光眼进行神经保护

• 批准号: 9430478
• 负责人: Yang Hu
• 金额: $ 36.08万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9430478
• 关键词: Acute; Address; Aftercare; Animal Model; Animals; Apoptosis; Axon; Binding Proteins; Biological Preservation; Blindness; CCAAT-Enhancer-Binding Proteins; Cell Death; Cell Survival; Cells; Cessation of life; Clinic; Clinical; Cytoprotection; Dependovirus; Disease; Employee Strikes; Endoplasmic Reticulum; Enzymes; Experimental Models; GRP78 gene; Glaucoma; Homologous Protein; Human; Individual; Inherited; Injection of therapeutic agent; Knockout Mice; Lesion; MAPK8 gene; Measurement; Mediating; Microspheres; Modeling; Morphology; Mus; Nerve Crush; Nerve Degeneration; Neurodegenerative Disorders; Ocular Hypertension; Optic Disk; Optic Nerve; Optic Nerve Injuries; Pathogenesis; Pathway interactions; Patients; Phosphotransferases; Physiologic Intraocular Pressure; Play; Positioning Attribute; Proteins; RNA Interference; Retina; Retinal Diseases; Retinal Ganglion Cells; Ribonucleases; Role; Secondary to; Signaling Molecule; Smooth Endoplasmic Reticulum; Testing; Therapeutic; Time; Tissues; Translating; Vision; Visual evoked cortical potential; Wallerian Degeneration; axon injury; axonal degeneration; clinically relevant; combinatorial; density; effective therapy; endoplasmic reticulum stress; experimental study; gene therapy; in vivo; injured; insight; interest; neuronal cell body; neuroprotection; novel; novel therapeutic intervention; prevent; protective effect; public health relevance; response; response to injury; targeted treatment; treatment effect; vector

DESCRIPTION (provided by applicant): Loss of vision in glaucoma is presumed to be due to compression of the optic nerve (ON) head by increased intraocular pressure (IOP), followed by ON degeneration and retrograde death of retinal ganglion cells (RGCs). A better understanding of the mechanisms underlying the RGC and ON degeneration is a prerequisite for developing novel neuroprotective treatments which is currently not available in clinics. Recently endoplasmic reticulum (ER) stress has been shown to play a critical role in neuronal degeneration. Striking RGC-protection has been accomplished by manipulating two key downstream molecules of ER stress, deleting CCAAT/enhancer binding protein homologous protein (CHOP) or activating X-box binding protein 1 (XBP-1). Of special interest, blocking the negative effects of ER stress also inhibited RGC death in a mouse glaucoma model. Thus targeting ER stress may have considerable therapeutic neuroprotective potential in glaucoma. This application will determine whether manipulating ER stress signaling molecules also rescue injured RGC axons in addition to RGC soma protection, through morphology and functional studies. Furthermore, efforts will be made to develop adeno-associated virus (AAV)-mediated gene therapies targeting ER stress to prevent neurodegeneration in mouse glaucoma models. New insights into the critical molecules that regulate RGC soma and axon survival can be translated into novel therapeutic approaches to prevent vision loss in patients with glaucoma.

描述(申请人提供)：青光眼患者的视力丧失被认为是由于眼压升高导致视神经压迫头部，继而是视网膜神经节细胞(RGC)变性和逆行死亡。更好地了解RGC和退行性病变的机制是开发新的神经保护疗法的先决条件，目前临床上还没有这种疗法。近年来，内质网应激在神经元退行性变中起重要作用。显著的RGC保护是通过操纵内质网应激的两个关键下游分子、删除CCAAT/增强子结合蛋白同源蛋白(CHOP)或激活X-box结合蛋白1(XBP-1)来实现的。特别有趣的是，阻断内质网应激的负面影响也抑制了小鼠青光眼模型中RGC的死亡。因此，靶向内质网应激可能对青光眼有相当大的治疗神经保护潜力。这一应用将通过形态和功能研究，确定操纵内质网应激信号分子除了保护RGC胞体外，是否还能挽救受损的RGC轴突。此外，将努力发展腺相关病毒(AAV)介导的针对内质网应激的基因治疗，以防止小鼠青光眼模型的神经退化。对调节RGC胞体和轴突存活的关键分子的新见解可以转化为预防青光眼患者视力丧失的新治疗方法。