Mechanisms of Retinal Neuronal Injury

项目名称：视网膜神经元损伤的机制 摘要 视网膜神经元死亡导致视力丧失和失明。但目前尚无有效治疗方法 视网膜神经元。本申请建议继续开展旨在阐明常见问题的项目 控制视网膜病变中视网膜神经元损伤的机制。在上一个资助期间，我们 证明内质网（ER）应激诱导的 CXL10/CXCR3 轴在视网膜中具有关键作用 炎症、氧化应激和神经元损伤。我们的数据提出了一个模型，其中受伤或压力 视网膜神经元（例如视网膜神经节细胞（RGC））释放 CXCL10，直接诱导 RGC 死亡 激活 cAMP/Epac1 通路并通过募集和激活间接导致 RGC 损伤 血液中的白细胞。 Epacs（Epac1 和 Epac2）是 cAMP 的新型介质。我们现在建议确定 Epac1 在将缺血性视网膜病的多重损伤与神经元损伤联系起来方面的核心作用，以及进一步 研究神经元和血管之间的相互作用。我们的假设是 Epac1 激活起着 缺血性视网膜病视网膜神经元和血管损伤的因果作用以及 Epac 的药理学抑制 为缺血性视网膜病提供了一种新的治疗干预方法。该应用程序将首次使用 Epac1 全局 KO 小鼠、Epac1 条件 KO 小鼠、AAV2 介导的基因传递、新型 Epac 抑制剂、非 侵入性先进成像和功能测试研究视网膜神经元中的 cAMP/Epac1 通路 急性和慢性缺血性视网膜病变小鼠模型中的血管损伤。它还将调查潜力 Epac1 诱导的视网膜神经元损伤和随后的血管改变的机制。该研究是 预计将显着促进对缺血性视网膜病变机制的理解，并应促进 开发保护缺血性视网膜病变中视网膜神经元和血管的新策略。这个 该提案直接涉及 NEI 出版物“视觉研究： 需求、差距和机遇”：1) 将分子生物学技术应用于 RGC 神经科学来剖析因素 对于生存、轴突再生和生理学都很重要。 2) 探索神经保护作为一种方法 延长 RGC 功能和存活率。

Project title: Mechanisms of Retinal Neuronal Injury 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.