Mechanisms of Retinal Neuronal Injury

总结 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，旨在阐明共同的 控制视网膜病变中视网膜神经元损伤的机制。在上一个财政年度，我们 研究表明，内质网（ER）应激诱导的CXL 10/CXCR 3轴在视网膜神经元凋亡中起关键作用。 炎症、氧化应激和神经元损伤。我们的数据表明，在一个模型中，受伤或压力 视网膜神经元（例如视网膜神经节细胞（RGC））释放CXCL 10，CXCL 10直接诱导RGC死亡， 激活cAMP/Epac 1通路，并通过募集和激活 血液中的白细胞Epacs（Epac 1和Epac 2）是cAMP的新介质。我们现在建议确定 Epac 1在将缺血性视网膜病变中的多次损伤与神经元损伤联系起来中的中心作用， 研究神经元和血管之间的相互作用。我们的假设是Epac 1激活在 缺血性视网膜病变中视网膜神经元和血管损伤的因果关系及Epac的药理学抑制作用 为缺血性视网膜病提供了新的治疗干预。该应用程序将首次使用 Epac 1全基因敲除小鼠，Epac 1条件性敲除小鼠，AAV 2介导的基因递送，新型Epac抑制剂， 有创先进成像和功能测试，以研究视网膜神经元中cAMP/Epac 1通路 急性和慢性缺血性视网膜病变小鼠模型的血管损伤。它还将调查潜在的 Epac 1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 预计将大大推进缺血性视网膜病变的机制理解，并应促进 保护缺血性视网膜病变中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出版物中确定的视觉研究优先事项，“视觉研究： 需求、差距和机会”：1）将分子生物学技术应用于RGC神经科学，剖析影响RGC神经系统的因素 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的功能和存活。

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.