Neuroprotection by Modulating ER Stress in Glaucoma

描述（由申请人提供）：青光眼的视力丧失被认为是由于眼压升高（IOP）压迫视神经（ON）头部，随后是视神经变性和视网膜神经节细胞（RGCs）逆行死亡。更好地了解RGC和ON变性的潜在机制是开发新的神经保护治疗的先决条件，目前尚无法在临床中使用。近年来，内质网应激已被证明在神经元变性中起关键作用。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)，可以实现rgc保护。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的RGC死亡。因此靶向内质网应激在青光眼治疗中可能具有相当大的神经保护潜力。该应用程序将通过形态学和功能研究确定操纵内质网应激信号分子除了保护RGC体细胞外，是否还能拯救受损的RGC轴突。此外，将努力开发针对内质网应激的腺相关病毒（AAV）介导的基因疗法来预防小鼠青光眼模型的神经退行性变。对调节RGC体细胞和轴突存活的关键分子的新见解可以转化为防止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.