Structure guided design of photoselectable channelrhodopsins
光选择性通道视紫红质的结构引导设计
基本信息
- 批准号:9244699
- 负责人:
- 金额:$ 23.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-09-30 至 2018-07-31
- 项目状态:已结题
- 来源:
- 关键词:AnimalsBRAIN initiativeBehaviorBrainCell Culture TechniquesCellsComplexCrystallographyDataDevelopmentDiseaseElectrophysiology (science)ElectrostaticsEngineeringEnvironmentFeelingFutureGenetic MarkersGoalsGrantHeadHealthKnowledgeLightLightingMammalian CellMethodsMotor CortexMusMutationNervous system structureNeuronsNeurosciencesOpsinOpticsOutcomePatternPhaseProcessPropertyProtein EngineeringResearchResolutionRetinalRoentgen RaysShapesStructureSynchrotronsTechnologyThinkingawakebeamlinebehavior influencebrain volumedesignflexibilityfree-electron laserin vivomeetingsmutantnervous system disorderneural circuitneuroregulationnovelnovel strategiesoptogeneticspreventprogramsprototyperelating to nervous systemsealtooltraittwo-photon
项目摘要
Project Summary:
This proposal outlines the development of a fundamentally new optogenetic technology capable
of flexibly manipulating the activity of thousands of neurons contributing to the dynamic activity
of distributed neural circuits with single neuron resolution.
No method that currently exists even
remotely meets the need of flexible, selective control of thousands of neurons distributed across
large volumes of the brain. Filling this methodological gap is a central research objective of the
BRAIN Initiative, because doing so will transform our ability to investigate how the nervous
system encodes, processes, utilizes, stores, and retrieves information.
The overall objective for this application is to acquire critical structural knowledge of photoactive
states of a red-shifted channelrhodopsin and use these to engineer a photoselectable channel
prototype that demonstrates the potential of our approach for future development in behaving
animals. This would allow opsin-expressing neurons to be flexibly selected, activated, and
deselected with light. By leveraging new structural knowledge, we anticipate that we can
develop a fundamentally new approach to optogenetics that takes us beyond genetically
targeted control and into an era of functionally targeted, flexible control of any neural ensemble.
The aims of our research are to obtain the first atomic structures of red-shifted channelrhodopsin
mutants in three channel states, engineer a three-state ReaChR mutant with high open
conductance and optimized action spectra, and demonstrate reversible photoselective control of
neurons in vivo with PReaChR prototypes.
We anticipate that completion of these aims will yield the following expected outcomes. First, it
will produce new knowledge of the underlying structural transformations between
channelrhodopsin photostates that will enable efficient computational design of photoselectable
optogenetic tools. Second, it will produce the first examples of photoselective
channelrhodopsins useful for neural excitation. Third, it will assess the utility of these new
opsins for flexible control of distributed sets of neurons. Collectively, these will provide a
roadmap to extending the transformative new trait of photoselectabilty to a wide range of
existing optogenetic tools for excitation, inhibition and modulation of neural activity. Further
research in this direction should ultimately enable flexible control of spatially complex
distributions of neurons in head-fixed and freely moving animals during behavior, a key to
furthering our understanding of the intricate neural dynamics that underlie our thoughts, feeling,
and actions and how circuit dynamics are disrupted by neurological disorders.
项目总结:
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Vadim Cherezov其他文献
Vadim Cherezov的其他文献
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Structural biology of G protein-coupled receptors
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- 批准号:
10396469 - 财政年份:2018
- 资助金额:
$ 23.1万 - 项目类别:
Structure guided design of photoselectable channelrhodopsins
光选择性通道视紫红质的结构引导设计
- 批准号:
9360611 - 财政年份:2016
- 资助金额:
$ 23.1万 - 项目类别:
HT structure determination of GPCRs by LCP serial femtosecond nanocrystallography
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- 批准号:
9078982 - 财政年份:2014
- 资助金额:
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HT structure determination of GPCRs by LCP serial femtosecond nanocrystallography
LCP 系列飞秒纳米晶体学测定 GPCR 的 HT 结构
- 批准号:
8612932 - 财政年份:2014
- 资助金额:
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