Neuroprotection by Modulating ER Stress in Glaucoma

通过调节 ER 应激对青光眼进行神经保护

基本信息

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
项目类别：
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

项目摘要

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）：假定青光眼视力丧失是由于眼内压（IOP）增加的视神经（ON）头部的压缩，然后是视网膜神经节细胞（RGC）的退化和逆行死亡。更好地理解RGC和退化的机制，是开发新型神经保护疗法的先决条件，目前在诊所中尚不可用。最近，内质网应力已显示在神经元变性中起关键作用。通过操纵ER应力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）来实现引人注目的RGC保护。特别感兴趣的是，阻止ER应力的负面影响也抑制了小鼠青光眼模型中的RGC死亡。因此，靶向ER应激可能在青光眼中具有相当大的治疗性神经保护潜力。该应用将确定是否通过形态和功能研究来操纵ER应力信号分子除了RGC SOMA保护外是否还挽救了受伤的RGC轴突。此外，将努力开发靶向ER应激的基因疗法（AAV）介导的基因疗法，以防止小鼠青光眼模型中的神经退行性。可以将调节RGC SOMA和轴突存活的关键分子的新见解转化为新型的治疗方法，以防止青光眼患者的视力丧失。