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: 10475753
• 负责人: RICHARD H KRAMER
• 金额: $ 47.03万
• 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 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10475753
• 关键词: Ablation; Acute; Age related macular degeneration; Alcoholism; Amacrine Cells; Animal Model; Behavior; Behavioral; Blindness; Brain; Cells; Chemicals; Clinical Research; Conscious; Contrast Sensitivity; Darkness; Degenerative Disorder; Disease; Disulfiram; Dominant-Negative Mutation; Electrophysiology (science); Enzymes; Eye; FDA approved; Frequencies; Functional disorder; Gene Expression; Generations; Genes; Genetic Transcription; Goals; Histologic; Human; Hyperactivity; Impairment; Individual; Interneurons; Light; Light Cell; Measures; Morphology; Mus; Neurons; Pharmaceutical Preparations; Pharmacotherapy; Phenotype; Photophobia; Photoreceptors; Process; Production; Proteins; Reporter; Reporting; Retina; Retinal Cone; Retinal Degeneration; Retinal Diseases; Retinal Ganglion Cells; Retinitis Pigmentosa; Retinoic Acid Receptor; Safety; Signal Pathway; Signal Transduction; Synapses; Testing; Tetracyclines; Therapeutic; Time; Toxic effect; Training; Transgenic Mice; Tretinoin; Viral; Vision; Visual; Visual impairment; avoidance behavior; behavior test; cellular targeting; experimental study; gene therapy; improved; in vivo; inhibitor; mouse model; multi-electrode arrays; optogenetics; patch clamp; photoreceptor degeneration; presynaptic neurons; receptor; response; retinal neuron; retinal rods; safety testing; small molecule; spatial vision; translation to humans; visual information

ABSTRACT 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.

抽象的 光反应在视杆细胞和视锥细胞光感受器中启动，由视网膜中间神经元处理，并通过突触 传输到视网膜神经节细胞（RGC），视网膜神经节细胞将信息以尖峰序列的形式发送到大脑。在 退行性视网膜疾病，包括年龄相关性黄斑变性 (AMD) 和色素性视网膜炎 (RP)，光感受器逐渐死亡，剥夺下游神经元的光敏感输入。然而， 最近的证据表明，失去光感受器只是这些疾病的问题的一部分。下游 视网膜神经元变得过度活跃，视网膜神经节细胞（RGC）在黑暗中自发放电，最高可达 比健康视网膜快 10 倍，破坏了视觉信息的正确编码。我们最近报道了 视黄酸 (RA) 是一种激活基因转录的小分子，是触发 RGC 的信号 多动症。体内阻断 RA 受体可以逆转多动症，揭示光反应 否则会被自发的 RGC 发射所掩盖。阻断视网膜中的 RA 受体也会增强 RP 小鼠模型中习得的视觉行为的对比敏感性。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 希望能够将患有退行性视网膜疾病的人类的有用视力延长多年。首先，我们会问是否 抑制 RA 信号传导不仅可以提高光敏感性，而且实际上可以改善有意识的视觉功能 视力受损的小鼠，通过对比敏感度和空间频率阈值的行为测试进行评估。我们 将确定 RA 抑制剂在变性过程中何时最有效，从而揭示最佳效果 开始治疗的时间。其次，我们将研究位于 RGC 上游的视网膜神经元，即 双极细胞和无长突细胞。我们将询问这些突触前神经元的病理生理变化是否 RA 信号传导升高也会诱导这些变化，以及抑制 RAR 是否可以逆转这些变化，提供 基因治疗有效细胞靶向的关键信息。第三，我们来测试一下视力是否可以 通过使用 FDA 批准的重新用途药物抑制合成 RA 的酶来改善 对于其他适应症，为人体临床研究铺平道路。总而言之，该项目将建立 增强视网膜退行性疾病视力的新治疗模式背后的原理验证。