Understanding how photoswitches restore visual function in blindness

了解光电开关如何恢复失明者的视觉功能

• 批准号: 10212754
• 负责人: RICHARD H KRAMER
• 金额: $ 27.19万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10212754
• 关键词: Action Potentials; Age related macular degeneration; Area; Behavior; Blindness; Brain; Calcium; Chemicals; Degenerative Disorder; Development; Disease; Exhibits; Face; Fire - disasters; Gene Expression; Goals; Human; Image; Injections; Ion Channel; Knowledge; Label; Light; Macular degeneration; Mediating; Mus; Names; Neurons; Operative Surgical Procedures; Optics; Patients; Pattern; Pharmaceutical Preparations; Photophobia; Photoreceptors; Photosensitization; Potassium Channel; Preclinical Testing; Property; Rest; Retina; Retinal Ganglion Cells; Retinitis Pigmentosa; Signal Transduction; Stimulus; Testing; Tissue Sample; Tissues; Toxic effect; Vertebrate Photoreceptors; Vision; Visual; Visual system structure; Work; blind; design; drug candidate; drug development; experimental study; human tissue; imaging study; improved; in vivo; in vivo imaging; mouse model; neural circuit; photoreceptor degeneration; response; restoration; retinal neuron; retinal stimulation; voltage gated channel

PROJECT SUMMARY Retinitis pigmentosa (RP) and age-related macular degeneration (AMD) are blinding diseases caused by the degeneration of rods and cones, leaving the rest of the visual system intact but unable to respond to light. A synthetic chemical photoswitch, named DENAQ, can restore visual responses in blind mouse models of RP. Previous studies showed that DENAQ imparts light-sensitivity on action potential firing in retinal ganglion cells (RGC), but how this occurs is unclear. The goal of this project is to elucidate the mechanism of DENAQ photosensitization, crucial for enabling discovery of improved drug candidates and for optimizing photo- stimulation strategies for vision restoration. The first aim is to understand why DENAQ selectively photosensitizes retinas from mice with dead rods and cones while having no effect on healthy retinas with intact rods and cones. We will test the hypothesis that degeneration leads to enhanced entry of DENAQ into RGCs and/or enhanced action on ion channels underlying spontaneous firing in RGCs. The second aim is to identify which RGCs are photosensitized by DENAQ. In the healthy retina, some RGCs fire at light onset, some at offset, and some at onset and offset. Studies will determine which are photosensitized by DENAQ, and whether local degeneration of rods and cones leads to spatially constrained RGC photosensitization, of particular relevance for AMD, a localized degenerative disease. Other studies will reveal whether DENAQ photosensitization applies to human RGCs in tissue samples obtained during surgical retinectomy. The third aim is to exploit our findings to optimize vision restoration. Information about the ion channels targeted by DENAQ will enable development of more specific photoswitches. Subcellular localization of these channels in RGCs will enable more spatially-precise photo-control. Finally imaging studies in vivo will reveal signals transmitted from the DENAQ-treated retina to the brain of blind mice, validating the functional integrity of the visual system and providing a platform for optimizing retinal stimulation patterns to best recapitulate normal visual responses.

项目摘要 色素性视网膜炎（RP）和与年龄相关的黄斑变性（AMD）是由盲目疾病引起的 杆和锥体的变性，使视觉系统的其余部分完好无损，但无法响应光。一个 合成化学照片开关（名为DENAQ）可以在RP的盲小鼠模型中恢复视觉响应。 先前的研究表明，DENAQ对视网膜神经节细胞的作用电势发射赋予了光敏性 （RGC），但是这是如何发生的。该项目的目的是阐明Denaq的机制 光敏化，对于能够发现改善的候选药物和优化照片至关重要 - 视力恢复的刺激策略。第一个目的是了解为什么Denaq有选择地 用死棒和锥体从小鼠那里获得光敏性视网膜，而对健康的视网膜没有影响 完整的杆和锥体。我们将检验以下假设，即变性会导致Denaq的进入 RGC和/或在RGC中自发射击的离子通道上的动作。第二个目标是 确定DENAQ光敏的RGC。在健康的视网膜中，一些RGC在轻度发作时发射 在抵消时，有些在开始和偏移时。研究将确定哪些是由Denaq光敏的，以及 杆和锥体的局部变性是否导致空间约束的RGC光敏化， 与局部退行性疾病AMD的特别相关。其他研究将揭示Denaq是否 光敏化适用于在手术视网膜切除术期间获得的组织样品中的人RGC。第三 目的是利用我们的发现来优化视力恢复。有关离子通道针对的离子通道的信息 Denaq将能够开发更具体的照片开关。这些通道的亚细胞定位 RGC将启用更多空间上的照片控制。最后，体内成像研究将揭示信号 从DENAQ处理的视网膜传输到盲小鼠的大脑，验证了功能完整性 视觉系统并提供一个平台，以优化视网膜刺激模式以最好地概括正常 视觉响应。