A new strategy for vision restoration based on melanopsin transduction mechanisms
基于黑视蛋白转导机制的视力恢复新策略
基本信息
- 批准号:10502717
- 负责人:
- 金额:$ 40万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-09-01 至 2026-06-30
- 项目状态:未结题
- 来源:
- 关键词:AnimalsBlindnessBrainCell DeathCellsCyclic NucleotidesDataDeath RateDominant-Negative MutationEffectivenessFOS geneFamilyFutureG-Protein-Coupled ReceptorsImageInflammatory ResponseIon ChannelKineticsKnowledgeLightMeasuresMediatingModalityModificationMonitorMusNamesPDE4A4Pathway interactionsPatternPhasePhotophobiaPhotoreceptorsPhotosensitivityPhototransductionProteinsRetinaRetinal DiseasesRetinal Ganglion CellsReverse Transcriptase Polymerase Chain ReactionSignal PathwaySignal TransductionSignaling MoleculeTestingTherapeuticVertebrate PhotoreceptorsViralVisionVisualWaterWorkactivity markerbasebehavior testcyclic-nucleotide gated ion channelsdensitygene therapyimmunocytochemistryimprovedinnovationknowledge baselight intensitymelanopsinmembermouse modelmulti-electrode arraysmutantnoveloptogeneticsoverexpressionpatch clampphotoactivationphotoreceptor degenerationrelating to nervous systemresponserestorationretinal neuronsight restorationtemporal measurementtheoriestreatment strategytrendvision aid
项目摘要
PROJECT SUMMARY
A pressing challenge in the treatment of retinal diseases is to restore vision in the retina with irreversible
photoreceptor degeneration. In theory, even in the absence of rods and cones, such diseased retina should still
be able to sense light through intrinsically photosensitive retinal ganglion cells (ipRGCs) using a photopigment
named melanopsin. However, the kinetics of melanopsin-mediated light response is slow, thus giving only very
poor temporal resolution and therefore largely limiting its ability to provide image-forming information. For the
same reason, a vision restoration approach previously proposed – which made use of virally expressed
melanopsin to endow light sensitivity to conventional retinal ganglion cells (RGCs) – is also limited by the slow
response kinetics of melanopsin. Our recent study has firmly established that melanopsin-mediated
phototransduction is rate-limited by its downstream components and that it can be accelerated by virally
expressed ion channels with faster kinetics. We propose to develop a novel vision restoration strategy by
accelerating melanopsin signaling via manipulating downstream transduction components in photoreceptor
degenerated mouse models. We have two major aims. In Aim 1, we shall focus on enhancing the light response
of endogenous melanopsin in M4- and M5-subtypes of ipRGCs because they have been shown to project to
image-forming brain centers, allowing them to contribute to the image-forming vision. We have discovered that
M4-cells respond to melanopsin photoactivation by elevating intracellular levels of cyclic nucleotides (cNMP) and
subsequent opening of cNMP-sensitive HCN channels. Our new preliminary data suggest that M5 cells also use
the HCN pathway. We have further shown that the response of the HCN-dependent signaling pathway can be
sped up by introducing a member of the cyclic nucleotide-gated channel family, CNGA2, resulting in faster
response kinetics and larger amplitudes, proving the concept of our strategy. In Aim 2, we shall restore light
response in conventional retinal ganglion cells using virally expressed melanopsin together with faster signaling
molecules. Our multielectrode array results show that simultaneously expressing melanopsin and CNGA2 in
cRGCs provides higher light sensitivities and faster rising phases than expressing melanopsin alone. Using
water-based vision-guided maze tests, we have further found that exogenous melanopsin and CNGA2 not only
restore light sensitivity but also confer pattern vision in photoreceptor-degenerated animals. Together, these
exciting preliminary observations raise the prospect of using CNG channels and/or modifications to other
phototransduction components of melanopsin as a therapeutic modality to restore vision following photoreceptor
degeneration. Innovation. All optogenetic approaches proposed thus far focus on finding a better light-sensing
protein with higher expression, better light sensitivity, and faster response kinetics. We are the first to exploit
downstream components and novel signaling molecules of melanopsin for vision restoration purposes. This
represents a conceptual innovation and an out-of-the-box strategy for vision restoration.
项目摘要
残留疾病治疗的紧迫挑战是,以不可逆
感光体变性。从理论上讲,即使在没有杆和锥体的情况下,这种患病的视网膜仍然应该
能够使用光学作用通过本质上光敏的残留神经节细胞(IPRGC)感知光
名为Melanopsin。但是,黑色素蛋白介导的光反应的动力学速度很慢,因此只给出了非常非常
暂时分辨率差,因此很大程度上限制了其提供图像形成信息的能力。为了
同样的原因,先前提出的视觉恢复方法 - 使用了几乎表达的
黑色素蛋白赋予对常规残留神经节细胞(RGC)的光敏度 - 也受慢速限制
黑色素蛋白的反应动力学。我们最近的研究首先确定了黑色素蛋白介导的
光转导的下游成分限制了速率,并且可以通过病毒加速
用更快的动力学表达离子通道。我们建议通过
通过操纵感光器中的下游转移成分加速黑色素蛋白信号传导
退化的小鼠模型。我们有两个主要目标。在AIM 1中,我们将专注于增强光反应
IPRGC的M4-和M5-亚型中的内源性黑色素蛋白,因为它们已被证明投影到
形成图像的大脑中心,使它们可以为图像形成视觉做出贡献。我们发现
M4细胞通过升高细胞内核苷酸(CNMP)和
随后开放CNMP敏感的HCN通道。我们的新初步数据表明M5细胞也使用
HCN途径。我们进一步表明,HCN依赖性信号通路的响应可以是
通过引入环状核苷酸门控通道家族的成员CNGA2加速,导致更快
响应动力学和更大的放大器,提供了我们战略的概念。在AIM 2中,我们将恢复光
使用虚拟表达的黑色素蛋白以及更快的信号传导的传统残留神经节细胞中的响应
分子。我们的多电极阵列结果表明,在
与单独表达黑色素蛋白相比,CRGC具有更高的光灵敏度和更快的上升阶段。使用
水基视觉引导的迷宫测试,我们进一步发现外源黑色素蛋白和CNGA2不仅
恢复光灵敏度,但也赋予光感受器脱生动物的模式视觉。在一起,这些
令人兴奋
黑色素蛋白的光转导成分是一种治疗方式,可在光感受之后恢复视力
退化。创新。迄今为止提出的所有光遗传学方法都集中于寻找更好的光感应
具有较高表达的蛋白质,更好的光灵敏度和更快的反应动力学。我们是第一个利用的人
黑色素蛋白的下游成分和新颖的信号分子,用于视觉恢复目的。这
代表了概念创新和视觉恢复的开箱即用策略。
项目成果
期刊论文数量(0)
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Zheng Jiang其他文献
Zheng Jiang的其他文献
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{{ truncateString('Zheng Jiang', 18)}}的其他基金
A new strategy for vision restoration based on melanopsin transduction mechanisms
基于黑视蛋白转导机制的视力恢复新策略
- 批准号:
10684846 - 财政年份:2022
- 资助金额:
$ 40万 - 项目类别:
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