Synthetic design of an all-optical electrophysiology system

全光学电生理系统的综合设计

• 批准号: 10225934
• 负责人: Baron Chanda
• 金额: $ 15.14万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-01 至 2022-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10225934
• 关键词: Back; Behavior; Biological; Cardiovascular system; Cells; Cellular Membrane; Chemicals; Chemistry; Complex; Crown Ethers; Development; Disease; Drug Screening; Electricity; Electrophysiology (science); Endocrine; Fluorescent Probes; Generations; Goals; Health; Heart; Human; Hybrids; Immune response; Inferior; Injections; Ion Channel; Ion Transport; Ionophores; Ions; Knowledge; Lead; Left; Light; Lipids; Liposomes; Mammalian Cell; Measurement; Measures; Membrane; Membrane Potentials; Methodology; Methods; Microelectrodes; Molecular Genetics; Monitor; Myocardial Contraction; Nervous system structure; Neurons; Neurosciences; Optics; Periodicity; Personal Satisfaction; Pharmacology; Process; Property; Research; Resolution; Rhodopsin; Science; Signal Transduction; Site; Stimulus; Synthesis Chemistry; System; Techniques; Testing; Time; Toxic effect; azobenzene; base; biological preparation; body system; cell type; chemical synthesis; design; engineering design; experimental study; flexibility; functional group; high-throughput drug screening; millisecond; neuronal circuitry; novel therapeutics; optogenetics; patch clamp; remote control; sensor; spiropyran; temporal measurement; tool; voltage

Project Summary/Abstract Optogenetics encompasses a broad array of tools and techniques that involve the use of light, in conjunction with molecular genetic tools, to drive and monitor activity of specific types of excitable cells in the nervous system and heart. Compared to traditional electrophysiological techniques, these methods are far less invasive and have the potential to monitor and manipulate electrical activity at multiple sites at the same time. The promise of optogenetics is not solely limited to expanding our basic understanding of complex organ systems but will also have a profound impact on the development of new therapeutics. Despite their promise, the current generation of optogenetic actuators are inferior compared to standard electrophysiological methods. While the membrane potential in a typical electrophysiological experiment can be changed by hundreds of millivolts on a sub- millisecond timescale, the current generation of light-activated ion channels are able to drive membrane potential by only a few millivolts in a millisecond. Much of the cutting-edge development in the field has focused on modifying and reengineering naturally-occurring ion channels, but these approaches have some inherent limitations. Herein, we propose to develop a new class of synthetic probes that serve as light-activated actuators for controlling membrane potential and ion concentrations with high temporal and spatial resolution. Employing a chemical synthesis approach towards these probes will allow us much greater flexibility to engineer and design more efficient actuators having the necessary throughput to drive cellular membrane potential. In addition, these chemical ion carriers can be combined with genetically encoded light-activated probes to provide even greater flexibility. The proposed research capitalizes on the expertise of a synthetic chemist (Prof. Schomaker, UW- Chemistry) and an ion channel electrophysiologist (Prof. Chanda, UW-Neuroscience). The two specific aims will focus on: a) the design and synthesis of photoactive ionophores and ion carriers, b) Characterization of the optical and transport properties of these designer ionophores and ion carriers.

项目概要/摘要 光遗传学包含广泛的工具和技术，涉及光的使用，结合 利用分子遗传工具，驱动和监测神经系统中特定类型可兴奋细胞的活动 和心。与传统的电生理技术相比，这些方法的侵入性要小得多，并且具有 同时监测和操纵多个部位的电活动的潜力。的承诺 光遗传学不仅限于扩展我们对复杂器官系统的基本理解，而且还将 对新疗法的开发产生深远的影响。尽管他们做出了承诺，但当前这一代人 与标准电生理方法相比，光遗传学执行器的性能较差。虽然膜 典型的电生理实验中的电位可以在子上改变数百毫伏。 毫秒时间尺度，当前一代光激活离子通道能够驱动膜电位 一毫秒内仅降低几毫伏。该领域的大部分前沿发展都集中在 修改和重新设计自然存在的离子通道，但这些方法有一些固有的 限制。在此，我们建议开发一类新型合成探针，用作光激活执行器 用于以高时间和空间分辨率控制膜电位和离子浓度。雇用 这些探针的化学合成方法将使我们能够更加灵活地进行工程和设计 更高效的执行器具有驱动细胞膜电位所需的吞吐量。此外，这些 化学离子载体可以与基因编码的光激活探针结合，以提供更大的 灵活性。拟议的研究利用了合成化学家（威斯康星大学 Schomaker 教授）的专业知识 化学）和离子通道电生理学家（昌达教授，威斯康辛大学神经科学）。这两个具体目标将 重点关注：a）光活性离子载体和离子载体的设计和合成，b）表征 这些设计离子载体和离子载体的光学和传输特性。