Targeting the retinoic acid signaling pathway for mitigating visual impairmen in retinal degenerative disorders

靶向视黄酸信号通路以减轻视网膜退行性疾病中的视力障碍

• 批准号: 10844853
• 负责人: RICHARD H KRAMER
• 金额: $ 19.85万
• 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 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10844853
• 关键词: Age related macular degeneration; Amacrine Cells; Award; Behavior; Brain; Cells; Clinical Research; Conscious; Contrast Sensitivity; Darkness; Degenerative Disorder; Disease; Enzyme Inhibition; FDA approved; Frequencies; Genes; Genetic Transcription; Goals; Human; Hyperactivity; Impairment; Interneurons; Light; Mus; Neurons; Parents; Pharmaceutical Preparations; Pharmacotherapy; Photophobia; Photoreceptors; Process; Production; Reporting; Retina; Retinal Cone; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Retinitis Pigmentosa; Retinoic Acid Receptor; Signal Pathway; Signal Transduction; Synaptic Transmission; Testing; Time; Training; Tretinoin; Vertebrate Photoreceptors; Vision; Visual; Visual impairment; behavior test; cellular targeting; drug repurposing; gene therapy; improved; in vivo; inhibitor; mouse model; presynaptic neurons; response; retinal neuron; small molecule; visual information; visual learning

ABSTRACT – NO CHANGE TO PARENT AWARD Light responses are initiated in rod and cone photoreceptors, processed by retinal interneurons, and synaptically transmitted to retinal ganglion cells (RGCs), which send information, in the form of spike trains, to the brain. In degenerative retinal disorders, including Age-related Macular Degeneration (AMD) and Retinitis Pigmentosa (RP), the photoreceptors gradually die off, depriving downstream neurons of light-sensitive input. However, recent evidence suggests that losing photoreceptors is only part of the problem in these disorders. Downstream retinal neurons become hyperactive, with retinal ganglion cells (RGCs) firing spontaneously in darkness at up to 10 times faster than in healthy retina, corrupting the proper encoding of visual information. We recently reported that retinoic acid (RA), a small molecule that activates gene transcription, is the signal that triggers RGC hyperactivity. Blocking the receptor for RA in vivo can reverse hyperactivity, unmasking light responses that would otherwise be obscured by spontaneous RGC firing. Blocking RA receptors in the retina also augments the contrast-sensitivity of learned visual behaviors in a mouse model of RP. Our goal in this project is to assess whether drugs or gene therapies that inhibit RA signaling can improve vision in mouse models of RP, with the hope of extending useful vision for years in humans with degenerative retinal disorders. First, we will ask whether inhibiting RA signaling not only improves light-sensitivity, but actually improves conscious visual function in vision-impaired mice, assessed with behavioral tests of contrast sensitivity and spatial frequency threshold. We will determine how when during the degeneration process RA inhibitors are most effective, revealing the optimal time for beginning treatment. Second, we will investigate retinal neurons that lie upstream of RGCs, namely bipolar cells and amacrine cells. We will ask whether pathophysiological changes in these presynaptic neurons are also induced by elevated RA signaling and whether inhibiting RAR can reverse these changes, providing critical information for effective cellular targeting of gene therapy. Third, we will test whether vision can be improved by inhibiting the enzyme that synthesizes RA, with a re-purposed drug that is already FDA-approved for other indications, paving the way for human clinical studies. Taken together, this project will establish the proof-of-principle behind a new treatment paradigm for augmenting vision in retinal degenerative disorders.

摘要 - 父母奖没有变化 光反应是在视网膜中间神经元处理的杆和锥形光感受器中启动的，并突触 传输到视网膜神经节细胞（RGC），这些细胞以尖峰火车的形式向大脑发送信息。 退化性视网膜疾病，包括与年龄相关的黄斑变性（AMD）和色素性视网膜炎 （RP），光感受器逐渐消失，剥夺了下游神经元的光敏输入。然而， 最近的证据表明，失去感光体只是这些疾病中问题的一部分。下游 视网膜神经元变得多动，视网膜神经节细胞（RGC）在黑暗中发射到 比健康视网膜快10倍，破坏了视觉信息的正确编码。我们最近报道 维甲酸（RA）是一种激活基因转录的小分子，是触发RGC的信号 多动症。阻止体内RA的接收器可以逆转多动症，从而揭示了光反应 否则，赞助RGC发射将掩盖。阻止视网膜中的RA接收器也增加 RP小鼠模型中学习的视觉行为的对比度敏感性。我们在这个项目中的目标是评估 抑制RA信号传导的药物或基因疗法是否可以改善RP小鼠模型的视力， 希望在患有退化性残留障碍的人类中扩展有用的愿景。首先，我们会问是否 抑制RA信号不仅可以改善光敏性，而且实际上改善了有意识的视觉功能 视力障碍小鼠，通过对比度灵敏度和空间频率阈值的行为测试进行评估。我们 将确定在变性过程中如何最有效的何时揭示最佳 开始治疗的时间。其次，我们将研究RGC上游的常规神经元，即 双极细胞和无长熟细胞。我们将询问这些突触前神经元中的病理生理变化是否 也是由升高的RA信号传导引起的，以及抑制RAR是否可以逆转这些变化 有效的基因治疗细胞靶向细胞靶向的关键信息。第三，我们将测试视力是否可以 通过抑制与已FDA批准的重新组合的药物合成RA的酶改进 对于其他适应症，为人类临床研究铺平了道路。综上所述，这个项目将确定 原则上的原则证明是一种新的治疗范式，用于增强永久退行性疾病的视力。