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（由申请人提供）：青光眼中的视力丧失被认为是由于眼内压（IOP）增加压迫视神经（ON）头，随后发生视神经变性和视网膜神经节细胞（RGC）逆行性死亡。更好地了解 RGC 和 ON 变性的机制是开发目前临床上尚不可用的新型神经保护疗法的先决条件。最近，内质网（ER）应激已被证明在神经元变性中发挥着关键作用。引人注目的 RGC 保护是通过操纵 ER 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，在小鼠青光眼模型中，阻断 ER 应激的负面影响也能抑制 RGC 死亡。因此，针对内质网应激可能对青光眼具有相当大的神经保护治疗潜力。该应用将通过形态和功能研究，确定除了 RGC 体细胞保护之外，操纵 ER 应激信号分子是否也能拯救受损的 RGC 轴突。此外，还将努力开发腺相关病毒（AAV）介导的针对内质网应激的基因疗法，以预防小鼠青光眼模型中的神经变性。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。