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.

项目概要 色素性视网膜炎（RP）和年龄相关性黄斑变性（AMD）是由视网膜色素变性引起的致盲性疾病 视杆细胞和视锥细胞退化，视觉系统的其余部分完好无损，但无法对光做出反应。一个 名为 DENAQ 的合成化学光开关可以恢复 RP 失明小鼠模型的视觉反应。 先前的研究表明，DENAQ 赋予视网膜神经节细胞动作电位放电光敏感性 （RGC），但尚不清楚这是如何发生的。该项目的目标是阐明 DENAQ 的机制 光敏性，对于发现改进的候选药物和优化光敏性至关重要 视力恢复的刺激策略。第一个目标是理解为什么 DENAQ 选择性地 使视杆细胞和视锥细胞死亡的小鼠的视网膜光敏化，同时对健康的视网膜没有影响 完整的视杆细胞和视锥细胞。我们将检验以下假设：变性导致 DENAQ 增强进入 RGC 和/或增强 RGC 自发放电离子通道的作用。第二个目标是 确定哪些 RGC 被 DENAQ 光敏化。在健康的视网膜中，一些 RGC 在光线开始时放电，另一些则在光线开始时放电。 在偏移处，以及一些在起始点和偏移处。研究将确定哪些是 DENAQ 光敏的，以及 视杆细胞和视锥细胞的局部变性是否会导致空间受限的 RGC 光敏化 与 AMD（一种局部退行性疾病）尤其相关。其他研究将揭示 DENAQ 是否 光敏作用适用于视网膜切除术期间获得的组织样本中的人类 RGC。第三个 目的是利用我们的发现来优化视力恢复。有关目标离子通道的信息 DENAQ 将有助于开发更具体的光电开关。这些通道的亚细胞定位 RGC 将实现更精确的空间光控制。最终体内成像研究将揭示信号 从经过 DENAQ 处理的视网膜传输到失明小鼠的大脑，验证了视网膜的功能完整性 视觉系统，并提供一个优化视网膜刺激模式的平台，以最好地再现正常情况 视觉反应。