Neuroprotection by Modulating ER Stress in 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）升高压迫视神经（ON）头，随后ON变性和视网膜神经节细胞（RGC）逆行死亡所致。更好地理解RGC和ON变性的机制是开发目前临床上不可用的新型神经保护治疗的先决条件。近年来研究表明内质网应激在神经元变性中起重要作用。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），已经实现了引人注目的RGC保护。特别有趣的是，阻断ER应激的负面作用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神经保护潜力。本申请将通过形态学和功能研究来确定除了RGC索马保护之外，操纵ER应激信号传导分子是否也拯救受损的RGC轴突。此外，将努力开发腺相关病毒（AAV）介导的靶向ER应激的基因疗法，以防止小鼠青光眼模型中的神经变性。对调节RGC索马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。

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.