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Next Generation Opto-GPCRs for Neuromodulatory Control

用于神经调节控制的下一代 Opto-GPCR

基本信息

批准号：
10515612
负责人：
Andre Berndt
金额：
$ 122.91万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-01-15 至 2026-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10515612
关键词：
Activities of Daily Living Acute Address Adoption Animals Arrestins BRAIN initiative Behavior Behavioral Behavioral Assay Biological Assay Biosensor Brain Brain Diseases Calcium Cell Culture Techniques Color Communication Communities Complex Coupled Coupling Cryoelectron Microscopy Databases Development Dissection Electrophysiology (science)Engineering Fiber G-Protein-Coupled Receptors GTP-Binding Proteins Goals Image In Vitro Ions Kinetics Laboratories Libraries Light Mammalian Cell Membrane Mutation Neuromodulator Neurons Neurosciences Neurotransmitters Opsin Optics Organism Pathway interactions Pharmacology Photometry Photophobia Physiology Property Protein Analysis Protein Engineering Publishing Receptor Signaling Resolution Rhodopsin Scheme Series Signal Pathway Signal Transduction Signaling Protein Site Slice Specificity Structural Biologist Structure Synapses System Techniques Technology Testing Time Translating Validation Variant Work awake behavior measurement biological systems brain tissue candidate selection cell type high throughput screening imaging approach in vivo innovation mutant neural neural circuit neuronal circuitry neurophysiology neuroregulation new technology next generation novel optogenetics receptor scaffold sensor simulation spatiotemporal structural biology tool translational potential two-photon

项目摘要

Project Summary/Abstract: The field of optogenetics — utilizing light to engage biological systems — is widely used for the dissection of neural circuits, cellular signaling and manipulating neurophysiological systems in awake, behaving animals. However, while many new opsins have been developed and are actively used, challenges still remain, and the current technology lacks a full toolbox for sub-cellular, spatiotemporal control of signaling — the predominant means for neuromodulator communication in the brain. Here we propose, an innovative effort combining neuroscience with structural biology and high-throughput pharmacology for the development of a series of cutting-edge novel Opto-GPCRs that will allow spatiotemporally precise and pathway-selective control of neuromodulator signaling in vitro and in freely moving animals. In four aims across five leading laboratories, we will develop and test these novel tools in vitro and in vivo. Specifically, we will work to 1) Develop and fully optimize OptoGPCR-v3.0 (Gi coupled) receptors for enhanced spectral multiplexing and altered sensitivity using structure-function analysis together with mutant-library HTS landing pad system; 2) Develop and fully optimize OptoGPCR-v3.0-Gq receptors for selective coupling to Gq signaling pathways using structure-guidance and the HTS landing pad system; 3) Utilize databases of less-explored naturally-occurring opsin-GPCRs to test, screen and further develop new optical tools with unique profiles; and 4) Assess the spectral compatibility for simultaneous use of OptoGPCR-v3.0 constructs in vivo, together with biosensors using photometry, 2p imaging and concurrent behavioral measures in vivo. Successful completion of the proposal will provide the wide neuroscience community with the long awaited capabilities of spatiotemporal manipulation of GPCR – neuromodulator signaling within neural circuits in vitro and in vivo, in awake freely behaving animals, and could be used for a wide variety of applications. This new technology will also further widen the field for unique optical approaches that allow discrete control and optodynamic simulation of neuromodulator function in brain tissue. We therefore believe that by the fulfilment of these goals we directly address the central purpose of this RFA-NS-21-027 call.

项目摘要/摘要：光遗传学是利用光来参与生物系统的研究领域