Genetically-Encoded, Non-Invasive and Wireless Modulation of Calcium Dynamics in Astrocytes With Spatiotemporal Precision and Depth

具有时空精度和深度的星形胶质细胞钙动态的基因编码、非侵入性无线调节

• 批准号: 10562265
• 负责人: CHUNLEI LIU
• 金额: $ 78.41万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-01 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10562265
• 关键词: Action Potentials; Address; Affect; Astrocytes; Behavior; Biochemical; Biophysics; Brain; Calcium; Calcium Signaling; Cations; Cell Membrane Permeability; Cells; Chronic; Complex; Coupled; Development; Disease; Electromagnetic Fields; Engineering; Event; Family; Ferritin; Foundations; Glutamates; Goals; Health; Heating; Image; In Vitro; Ion Channel; Ions; Iron; Knowledge; Mediating; Membrane; Membrane Proteins; Modeling; Modernization; Molecular; Morphologic artifacts; Names; Neurodegenerative Disorders; Neurons; Neurotransmitters; Outcome; Pattern; Permeability; Physiological; Proteins; Regulation; Research; Role; Signal Transduction; Source; Supporting Cell; Synapses; Synaptic Transmission; TRP channel; Techniques; Technology; Tissues; Treatment Efficacy; cell type; improved; in vivo; nervous system disorder; neural; neural circuit; neuronal circuitry; neuropsychiatric disorder; neurotransmitter release; new therapeutic target; radio frequency; sound; spatiotemporal; synaptic function; therapeutic target; tool; two-photon; wireless

Abstract Astrocytes are the most abundant cell types in the brain and have long been thought as primarily passive support cells. Studies in the past two decades leveraging modern techniques have revealed crucial roles for astrocytes in neuronal circuit assembly, synaptic function and behavior. Aberrant astrocytic function is implicated in neuropsychiatric and neurodegenerative diseases, and astrocytes hold great promises as novel therapeutic targets for improving treatment efficacy. Despite this progress, a deeper mechanistic understanding of astrocytes' causative and correlative roles in operating neural circuitry and their contribution to behavior is still lacking. This knowledge gap is largely due to the lack of technologies to effectively manipulate astrocyte activity with cell-type and temporal precision. The physiological hallmark of astrocytes is their complex spatiotemporal patterns of intracellular and intercellular calcium signaling crucial to their bidirectional interaction with neurons. The objective of this project is to develop a non-invasive, wireless and genetically encoded actuator to modulate astrocytic activity with cell-type and temporal precision in vivo. Our approach, named FeRIC (Ferritin iron Redistribution to Ion Channels), combines the use of radiofrequency (RF) waves and ion channels to control membrane ion permeability non-invasively and wirelessly. The FeRIC technique utilizes RF waves to activate membrane proteins that are coupled to the endogenous cellular iron storage protein ferritin. Our preliminary studies have demonstrated the feasibility of FeRIC-mediated RF stimulation to modulate calcium activities in astrocytes and astrocytic networks that resembles those observed under physiological conditions. Further, FeRIC-mediated RF stimulation of astrocytes has been able to elicit neurotransmitter release and evoke action potentials in connected neurons. We aim to develop a set of molecular tools and characterize their abilities 1) to modulate global calcium signaling in astrocytes, 2) to modulate microdomain calcium activities in astrocytes and 3) to modulate astrocyte-neuron interactions at the tripartite synapses in vivo. If successful, the project will develop a non-invasive and genetically encoded molecular tool to modulate astrocytic activity with cell-type and temporal precision. We will elucidate the biophysical underpinnings of the mechanism. The project will have a broad impact to the study of the roles of astrocytes in health and disease.

摘要 星形胶质细胞是大脑中最丰富的细胞类型，长期以来一直被认为主要是被动支持 细胞过去二十年利用现代技术的研究揭示了星形胶质细胞的关键作用 神经元电路组装、突触功能和行为。异常的星形胶质细胞功能与 神经精神和神经退行性疾病，星形胶质细胞作为新的治疗药物有很大的希望。 提高治疗效果的目标。尽管取得了这一进展，但更深层次的机械理解， 星形胶质细胞在操作神经回路中的原因和相关作用及其对行为的贡献仍然是 缺乏这种知识差距很大程度上是由于缺乏有效操纵星形胶质细胞活性的技术 以细胞类型和时间精度。星形胶质细胞的生理特征是其复杂的时空 细胞内和细胞间钙信号传导的模式对它们与神经元的双向相互作用至关重要。 本项目的目标是开发一种非侵入性的、无线的和基因编码的致动器来调节 星形胶质细胞活性与细胞类型和体内时间精确度。我们的方法，命名为铁（铁蛋白铁 重新分配到离子通道），结合使用射频（RF）波和离子通道，以控制 膜离子渗透性的非侵入性和无线。FeRIC技术利用RF波激活 与内源性细胞铁储存蛋白铁蛋白偶联的膜蛋白。我们的初步 研究已经证明了FeRIC介导的RF刺激调节心肌细胞中钙活性的可行性， 星形胶质细胞和星形胶质细胞网络类似于在生理条件下观察到的那些。此外，本发明还 星形胶质细胞的FeRIC介导的RF刺激能够引起神经递质释放并引起动作 连接神经元的电位。我们的目标是开发一套分子工具，并表征它们的能力：1） 调节星形胶质细胞中的整体钙信号传导，2）调节星形胶质细胞中的微区钙活性， 3)以调节体内三重突触处的星形胶质细胞-神经元相互作用。如果成功，该项目将 开发一种非侵入性和遗传编码的分子工具，以调节星形胶质细胞的活性与细胞类型， 时间精度我们将阐明该机制的生物物理基础。该项目将有一个 对研究星形胶质细胞在健康和疾病中的作用产生广泛影响。