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

基本信息

  • 批准号:
    10298375
  • 负责人:
  • 金额:
    $ 48.48万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

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.
摘要 光反应在视杆和视锥光感受器中启动,由视网膜中间神经元和突触处理 这些信号被传递到视网膜神经节细胞(RGC),视网膜神经节细胞以尖峰序列的形式向大脑发送信息。在 退行性视网膜疾病,包括黄斑变性(AMD)和色素性视网膜炎 (RP)光感受器逐渐死亡,剥夺了下游神经元的光敏输入。然而,在这方面, 最近的证据表明,失去光感受器只是这些疾病的部分问题。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, 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 视黄酸(RA),一种激活基因转录的小分子,是触发RGC的信号 多动症。在体内阻断RA受体可以逆转过度活跃,揭示光反应, 否则会被RGC的自发发射所掩盖。阻断视网膜中的RA受体也会增强 在RP小鼠模型中学习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, 希望能延长患有退行性视网膜疾病的人的有效视力。首先,我们会问, 抑制RA信号不仅改善了光敏感性,而且实际上改善了有意识的视觉功能。 视觉受损小鼠,用对比敏感度和空间频率阈值的行为测试进行评估。我们 将确定在退化过程中RA抑制剂何时最有效,揭示最佳的 开始治疗的时间。其次,我们将研究位于RGCs上游的视网膜神经元,即 双极细胞和无长突细胞。我们会问这些突触前神经元的病理生理变化 也是由升高的RA信号传导诱导的,以及抑制RAR是否可以逆转这些变化, 基因治疗的有效细胞靶向的关键信息。第三,我们将测试视觉是否可以 通过抑制合成类风湿关节炎的酶,用一种已经被FDA批准的重新用途的药物来改善 用于其他适应症,为人类临床研究铺平道路。总的来说,该项目将建立 一种新的治疗模式背后的原理证明,用于增强视网膜退行性疾病的视力。

项目成果

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RICHARD H KRAMER其他文献

RICHARD H KRAMER的其他文献

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{{ truncateString('RICHARD H KRAMER', 18)}}的其他基金

An electro-mechanical mechanism of spike propagation in myelinated axons
有髓轴突中尖峰传播的机电机制
  • 批准号:
    10194107
  • 财政年份:
    2021
  • 资助金额:
    $ 48.48万
  • 项目类别:
Probing GABAa receptor function and plasticity with light
用光探测 GABAa 受体功能和可塑性
  • 批准号:
    9286699
  • 财政年份:
    2017
  • 资助金额:
    $ 48.48万
  • 项目类别:
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
  • 财政年份:
    2015
  • 资助金额:
    $ 48.48万
  • 项目类别:
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
  • 财政年份:
    2015
  • 资助金额:
    $ 48.48万
  • 项目类别:
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
  • 财政年份:
    2015
  • 资助金额:
    $ 48.48万
  • 项目类别:
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
  • 财政年份:
    2015
  • 资助金额:
    $ 48.48万
  • 项目类别:
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:
    10684166
  • 财政年份:
    2015
  • 资助金额:
    $ 48.48万
  • 项目类别:
A universal photoswitch system for optical control of neuronal receptors
用于神经元受体光学控制的通用光电开关系统
  • 批准号:
    7726422
  • 财政年份:
    2009
  • 资助金额:
    $ 48.48万
  • 项目类别:
A universal photoswitch system for optical control of neuronal receptors
用于神经元受体光学控制的通用光电开关系统
  • 批准号:
    8255457
  • 财政年份:
    2009
  • 资助金额:
    $ 48.48万
  • 项目类别:
A universal photoswitch system for optical control of neuronal receptors
用于神经元受体光学控制的通用光电开关系统
  • 批准号:
    7898562
  • 财政年份:
    2009
  • 资助金额:
    $ 48.48万
  • 项目类别:

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