Light-activated ion chanenls for remote control of neuronal activity

描述（由申请人提供）：神经元拥有离子通道，这些离子通道可被电压、配体、温度和机械力直接激活，但不能被光激活。在这个项目中，我们的目标是结合有机化学和分子生物学来设计可以直接由光调节的新型离子通道。然后，我们将使用这些通道来回答目前可用方法无法解决的有关视网膜活动依赖突触可塑性的问题。具体来说，这个项目将做出几项重大贡献。它将增加不断增长的光激活通道工具箱，这些通道在远程控制神经元活动的不同方面具有很大的效用。2)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接的还是随使用而改变的。3)它将阐明突触内稳态是在树突树的一部分局部起作用，还是在整个神经元中全局起作用，为海马体和视网膜内稳态可塑性的功能重要性和机制提供线索。4)阐明色素性视网膜炎小鼠和大鼠模型中由于光感受器变性而发生的视网膜回路生理学变化。通过阐明视网膜重塑的功能效应和时间过程，本研究将为评估和设计依赖于视网膜完整突触信号的新治疗策略提供重要信息，包括恢复光感受器功能的基因治疗和再生视杆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，使神经细胞能够和光打开和关闭。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，以及在诸如色素性视网膜炎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。这将为了解视网膜如何功能和适应不同的光照条件提供基础信息，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.