Understanding How Photoswitches Restore Visual Function in Blind Mice

了解光电开关如何恢复失明小鼠的视觉功能

• 批准号: 9330653
• 负责人: RICHARD H KRAMER
• 金额: $ 7.8万
• 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 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9330653
• 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; Health; Human; Image; Injection of therapeutic agent; Ion Channel; Knowledge; Label; Left; 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; Retinal Ganglion Cells; Retinitis Pigmentosa; Signal Transduction; Stimulus; Testing; Tissue Sample; Tissues; Toxic effect; Vertebrate Photoreceptors; Vision; Visual; Visual system structure; Work; blind; cone-rod degeneration; design; drug candidate; drug development; human tissue; improved; in vivo; in vivo imaging; mouse model; neural circuit; photoreceptor degeneration; research study; response; restoration; retinal neuron; voltage gated channel

 DESCRIPTION (provided by applicant): 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 i 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 stimulatin patterns to best recapitulate normal visual responses.

 描述（由申请人提供）：色素性视网膜炎（RP）和年龄相关性黄斑变性（AMD）是由视杆细胞和视锥细胞退化引起的致盲性疾病，视觉系统的其余部分完好无损，但无法对光做出反应。一种名为 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 (RGC) 动作电位放电光敏感性，但其如何发生尚不清楚。该项目的目标是阐明 DENAQ 光敏作用机制，这对于发现改进的候选药物和优化视力恢复的光刺激策略至关重要。第一个目标是了解为什么 DENAQ 选择性地对视杆细胞和视锥细胞死亡的小鼠的视网膜进行光敏化，而对视杆细胞和视锥细胞完整的健康视网膜没有影响。我们将测试以下假设：变性导致 DENAQ 进入 RGC 的增强和/或对 RGC 中自发放电的离子通道的作用增强。第二个目的是确定哪些 RGC 对 DENAQ 光敏。在健康的视网膜中，一些 RGC 在光线开始时放电，一些在光线偏移时放电，一些在光线开始和偏移时放电。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，这与 AMD（一种局部退行性疾病）特别相关。其他研究将揭示 DENAQ 光敏化是否适用于视网膜切除术期间获得的组织样本中的人类 RGC。第三个目标是利用我们的发现来优化视力恢复。有关 DENAQ 所针对的离子通道的信息将有助于开发更具体的光电开关。 RGC 中这些通道的亚细胞定位将实现更空间精确的光控制。最后，体内成像研究将揭示从 DENAQ 处理的视网膜传输到失明小鼠大脑的信号，验证视觉系统的功能完整性，并为优化视网膜刺激模式以最好地重现正常视觉反应提供平台。