Light-activated ion chanenls for remote control of neuronal activity

描述（由申请人提供）：神经元具有直接由电压、配体、温度和机械力激活的离子通道，但不受光激活。我们在这个项目中的目标是使用有机化学和分子生物学的组合来设计可以直接由光调节的新型离子通道。然后，我们将使用这些渠道来回答问题，集中在视网膜的活动依赖性突触可塑性，是目前可用的方法无法接近。具体而言，该项目将作出几项重大贡献。1)它将增加光激活通道的不断增长的工具箱，这些通道对于远程控制神经元活动的不同方面非常有用。2)它将阐明视网膜神经节细胞是否像海马神经元一样表现出稳态突触可塑性，揭示视网膜中的突触是硬连线的还是可以随着使用而改变。3)它将阐明突触内稳态是否在树突树的一部分内局部运作，或仅在整个神经元中全局运作，为海马和视网膜内稳态可塑性的功能重要性和机制提供线索。4)它将阐明视网膜电路的生理变化，发生作为视网膜色素变性的小鼠和大鼠模型中的光感受器变性的结果。通过阐明视网膜重塑的功能效应和时间过程，这项研究将为评估和设计新的治疗策略提供重要信息，这些策略依赖于通过视网膜的完整突触信号传导，包括用于恢复感光细胞功能的基因治疗和用于再生视杆细胞或视锥细胞的干细胞治疗。 公共卫生相关性：在这个项目中，我们将设计新的分子，使神经细胞能够用光打开和关闭。我们将使用这些工具来回答一些重要的问题，如神经细胞之间的突触连接如何随着活动而变化，以及在视网膜色素变性等退行性致盲疾病中，视杆细胞和视锥细胞丢失后，通过视网膜的信号如何变化。这将为理解视网膜如何发挥作用和适应不同的光线条件提供基本信息，并将有助于设计和评估未来恢复视力的治疗策略。

DESCRIPTION (provided by applicant): Neurons possess ion channels that are directly activated by voltage, ligands, temperature, and mechanical forces, but not by light. Our goal in this project is to use a combination of organic chemistry and molecular biology to engineer new types of ion channels that can be directly regulated by light. We will then use these channels to answer questions focused on activity dependent synaptic plasticity in the retina that are unapproachable with presently available methods. Specifically, this project will make several major contributions. 1) It will add to the growing toolbox of light-activated channels that are of great utility for remote control of different aspects of neuronal activity. 2) It will elucidate whether retinal ganglion cells, like hippocampal neurons, exhibit homeostatic synaptic plasticity, revealing whether synapses in the retina are hard-wired or can change with use. 3) It will elucidate whether synaptic homeostasis operates locally within a portion of a dendritic tree, or only globally, across an entire neuron, providing clues as to the functional importance and mechanism of homeostatic plasticity in the hippocampus and retina. 4) It will elucidate the changes in the physiology of the retinal circuit that occur as a consequence of photoreceptor degeneration in mouse and rat models of retinitis pigmentosa. By elucidating the functional effects and time course of retinal remodeling, this study will provide information of key importance for evaluating and designing new therapeutic strategies that rely on intact synaptic signaling through the retina, including gene therapy for restoring photoreceptor function and stem cell therapy for regenerating rod or cones. PUBLIC HEALTH RELEVANCE: In this project we will engineer new molecules that will allow nerve cells to be turned on and off with light. We will use these tools to answer important questions about how synaptic connections between nerve cells change with activity and how signaling through the retina changes after rods and cones are lost during degenerative blinding diseases such as retinitis pigmentosa. This will provide fundamental information for understanding how the retina functions and adapts to different light conditions and will be useful for designing and evaluating future therapeutic strategies for restoring vision.