Neuroprotection by Modulating ER Stress in Glaucoma

项目摘要 青光眼是最常见的不可逆性失明的原因，将影响超过1亿人 到2040年，40到80岁之间。由于视神经变性（ON），它会导致严重的视力丧失， 视网膜神经节细胞（RGCs）。对于神经保护剂存在显著的未满足的临床需求。我们以前的 ON创伤性损伤和青光眼的研究表明，急性和慢性ON损伤均诱导 内质网（ER）应激。我们能够保护受伤的RGC索马和轴突， 阻断了ER应激的不利影响，通过操纵两个关键的下游分子的未折叠的 a）CCAAT/增强子结合蛋白同源蛋白的缺失 （CHOP），和/或B）X盒结合蛋白1（XBP-1）的活化。因此，轴突损伤诱导的内质网应激可能是一个重要因素。 神经元损伤的共同机制和靶向神经元ER应激可能具有相当大的治疗作用 轴突病相关疾病的神经保护潜力。作为第一步，我们建议确定 通过基于细胞的高通量筛选（HTS）筛选化学文库的新型ER应激调节剂 然后验证这些药物是否促进RGC和ON存活并保护视觉功能 在小鼠青光眼模型中。最近，令人兴奋的关于轴突沃勒变性的最新研究表明， 参与轴突NAD+代谢的几种关键分子对轴突变性至关重要。SARM1 （不育α和TIR基序1），例如，由轴突NAD+合成酶负调控 烟酰胺单核苷酸腺苷酰转移酶2（NMNAT 2）诱导轴突变性; SARM 1或轴突NMNAT的激活导致轴突保护。因此，我们将测试假设， 调节内源性神经元ER应激和NAD+代谢将协同防止两者 青光眼视网膜神经节细胞索马和轴突（ON）变性与视力保护这项研究可能会产生新的 组合治疗策略，导致患者更有效的神经保护。最后，我们将 为RGC形态和功能研究开发新的体内成像工具，并获得急需的 深入了解RGC ER应激启动的机制。我们希望通过这些研究的结果将 为ER应激调控的临床应用提供必要的信息，并建立可翻译的 这些技术和生物标志物将极大地促进青光眼患者的临床管理。

PROJECT SUMMARY Glaucoma is the most common cause of irreversible blindness and will affect more than 100 million people between 40 to 80 years old by 2040. It causes severe visual loss due to degeneration of optic nerve (ON) and retinal ganglion cells (RGCs). There is a significant unmet clinical need for neuroprotectants. Our previous studies of ON traumatic injury and glaucoma demonstrated that both acute and chronic ON injury induce endoplasmic reticulum (ER) stress in RGCs. We were able to protect the injured RGC soma and axons if we blocked the detrimental effects of ER stress by manipulating two key downstream molecules of the unfolded protein response (UPR) in opposite ways: a) deletion of CCAAT/enhancer binding protein homologous protein (CHOP), and/or b) activation of X-box binding protein 1 (XBP-1). Thus axon injury-induced ER stress may be a common mechanism of neuronal damage and targeting neuronal ER stress may have considerable therapeutic neuroprotective potential in diseases associated with axonopathy. As the first step, we propose to identify novel ER stress modulators by screening chemical libraries with cell-based high throughput screen (HTS) assays; and then to validate whether these agents promote RGC and ON survival and preserve visual function in mouse glaucoma models. Recently, exciting recent studies of axonal Wallerian degeneration have shown that several key molecules involved in axonal NAD+ metabolism are critical for axonal degeneration. SARM1 (Sterile Alpha and TIR Motif 1), for example, is negatively regulated by axonal NAD+ synthetic enzyme nicotinamide mononucleotide adenylyltransferase 2 (NMNAT2) to induce axon degeneration; deletion of SARM1 or activation of axonal NMNATs results in axon protection. Thus, we will test the hypothesis that modulating both intrinsic neuronal ER stress and NAD+ metabolism will synergistically prevent both RGC soma and axon (ON) degeneration and preserve vision in glaucoma. This study may generate novel combinatory therapeutic strategies that lead to more efficient neuroprotection in patients. And finally, we will develop novel in vivo imaging tools for RGC morphology and function studies and acquire much needed insights into the mechanism of RGC ER stress initiation. We expect the results through these studies will provide essential information for clinical application of ER stress modulation, and establish translatable techniques and biomarkers that will greatly facilitate clinical management of glaucoma patients.