Mechanisms of Retinal Neuronal Injury

摘要 视网膜神经元死亡会导致视力丧失和失明。然而，目前还没有有效的治疗方法来保护 视网膜神经元。本申请建议继续一个项目，旨在阐明共同 视网膜病变中控制视网膜神经元损伤的机制。在上一个资助期内，我们 内质网应激诱导的CXL10/CXCR3轴在视网膜中起关键作用 炎症、氧化应激和神经元损伤。我们的数据表明，在这个模型中，受伤或压力 视网膜神经元(如视网膜神经节细胞)释放CXCL10，通过以下途径直接诱导RGC死亡 激活cAMP/Epac1通路，通过募集和激活间接造成RGC损伤 血液中的白细胞。Epacs(Epac1和Epac2)是cAMP的新介体。我们现在建议确定 Epac1在缺血性视网膜病变的多种损伤与神经元损伤之间的联系中的中心作用 研究神经元和血管之间的相互作用。我们的假设是Epac1的激活起到了 缺血性视网膜病视网膜神经元和血管损伤的因果关系及EPAC的药理抑制作用 为治疗缺血性视网膜病变提供了一种新的治疗手段。此应用程序将首次使用 Epac1全局性KO小鼠，Epac1条件性KO小鼠，AAV2介导的基因传递，新型EPAC抑制剂，非 侵入性高级成像和功能测试研究视网膜神经元cAMP/Epac1通路 以及急性和慢性缺血性视网膜病变小鼠模型中的血管损伤。它还将调查潜在的 Epac1诱导的视网膜神经元损伤和随后的血管改变的机制。这项研究是 有望显著促进对缺血性视网膜病变的机制理解，并应促进 在缺血性视网膜病变中保护视网膜神经元和血管的新策略的发展。这 该提案直接涉及NEI出版物“Vision Research： 需要、差距和机会“：1)将分子生物学技术应用于RGC神经科学，剖析因素 对生存、轴突再生和生理学很重要。2)探索神经保护作为一种方法 延长RGC功能，延长生存期。

SUMMARY Retinal neuronal death causes vision loss and blindness. Yet there is no therapy available to effectively protect retinal neurons. This application proposes continuation of a project designed to elucidate common mechanisms that control retinal neuronal injury in retinopathy. During the previous funding period, we demonstrated that endoplasmic reticulum (ER) stress-induced CXL10/CXCR3 axis has a key role in retinal inflammation, oxidative stress and neuronal injury. Our data suggest a model in which injured or stressed retinal neurons (e.g. retinal ganglion cells (RGCs)) release CXCL10 that directly induces RGC death by activating the cAMP/Epac1 pathway and indirectly causes RGC damage by recruiting and activating leukocytes from blood. Epacs (Epac1 and Epac2) are novel mediators of cAMP. We now propose to determine the central role of Epac1 in linking multiple insults in ischemic retinopathy to neuronal injury and further investigate the interactions between neurons and vessels. Our hypothesis is that Epac1 activation plays a causal role in retinal neuronal and vascular injury in ischemic retinopathy and pharmacologic inhibition of Epac provides a novel therapeutic intervention for ischemic retinopathy. This application will, for the first time, use Epac1 global KO mice, Epac1 conditional KO mice, AAV2-mediated gene delivery, novel Epac inhibitor, non- invasive advanced imaging and functional testing to investigate the cAMP/Epac1 pathway in retinal neuronal and vascular injury in mouse models of acute and chronic ischemic retinopathy. It will also investigate potential mechanisms of Epac1-induced retinal neuronal damage and subsequent vascular alterations. The research is expected to significantly advance the mechanistic understanding of ischemic retinopathy and should facilitate the development of novel strategies to protect retinal neurons and vessels in ischemic retinopathy. This proposal directly addresses vision research priorities identified in the NEI Publication, “Vision Research: Needs, Gaps, & Opportunities”: 1) Apply molecular biology techniques to RGC neuroscience to dissect factors important for survival, axon regeneration, and physiology. 2) Explore neuroprotection as an approach for prolonging RGC function and survival.