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Real-Time Detection of Glutamate using Templated Polymers as Shape-Changing Target Receptors

使用模板聚合物作为变形目标受体实时检测谷氨酸

基本信息

批准号：
10532757
负责人：
Edward Song
金额：
$ 21.92万
依托单位：
UNIVERSITY OF NEW HAMPSHIRE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2024-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10532757
关键词：
Address Adenosine Affinity Alzheimer&apos s Disease Benchmarking Binding Binding Sites Brain Brain Diseases Catecholamines Chemicals Communication Complement Data Detection Development Diffusion Dopamine Ensure Environment Enzymes Extracellular Space Frequencies Future Glutamate Receptor Glutamates Goals Hippocampus In Vitro Label Length Longevity Measurement Measures Mental disorders Methods Microdialysis Microelectrodes Modeling Molecular Molecular Conformation Monitor Morphology Neurofibrillary Tangles Neurons Neurotransmitters Outcome Oxidation-Reduction Parkinson Disease Pathway interactions Performance Periodicity Physiologic pulse Physiological Polymers Process Public Health Reaction Time Reporter Research Resolution Sampling Scanning Serotonin Shapes Signal Transduction Slice Specificity Spectrum Analysis Stimulus Synapses Synaptic Cleft System Techniques Technology Time Transducers Validation Work aptamer autism spectrum disorder brain tissue clinical application copolymer design detection limit electric impedance extracellular ferrocene improved in vivo in vivo monitoring liquid chromatography mass spectrometry millisecond monomer mouse model nervous system disorder neurochemistry novel novel strategies patch clamp polymerization real time monitoring receptor receptor binding sensor sensor technology success technology platform temporal measurement uptake

项目摘要

PROJECT SUMMARY / ABSTRACT There is a great demand for a new sensing technology that can monitor neurochemicals in brain continuously in real-time with high temporal resolution. While electrochemical detection of electroactive neurotransmitters (such as dopamine and serotonin) have been successful using high frequency voltammetric methods (such as fast- scan cyclic voltammetry), measurement of non-electroactive species (such as glutamate) still remain a great challenge for achieving real-time monitoring with high time resolution. The goal of this project is to implement a new electrochemical sensing platform that can monitor glutamate, a well-known non-electroactive neurotransmitter, with physiologically relevant detection range and high temporal resolution. The proposed sensing approach can serve as an alternative to enzymatic sensing or microdialysis which have some limitations with respect to time resolution and stability. Motivated in part by the aptamer-based electrochemical sensors, the proposed sensing mechanism utilizes a novel synthetic target receptor as both a target recognition unit and a signal transducer. The glutamate receptor is formed by a single-chain stimuli-responsive templated polymer that binds specifically to its template molecule, namely, glutamate. Furthermore, upon selective target recognition, the polymer undergoes conformation change (from linear to folded shape). This change in polymer morphology can be electrochemically detected through the use of a redox reporter (such as ferrocene) attached to the polymer. For validation of the proposed sensing approach, the developed sensor will be compared against two well-established methods, a patch clamp and a microdialysis technique. A patch clamp system is ideal for measuring fast dynamics (milliseconds) of chemical exchange at the synaptic cleft of the neurons, however, lacks chemical specificity. A microdialysis in conjunction with liquid chromatography and mass spectrometry provides exceptional chemical specificity, however, the temporal resolution is poor (on the order of minutes). It is expected that the developed sensor platform will be able to bridge the gap between these two existing methods and to provide versatility in sensing performances. The goals of this project will be achieved by pursuing the following specific aims: (1) optimization of the templated polymer-based glutamate receptor to meet the desired performance metrics; and (2) validation of the developed glutamate sensor in a physiological environment. The successful outcome of this project will be the development of a new general platform technology for detection of neurochemicals in real-time with a time resolution that is sufficient for studying synaptic communications as well as for monitoring chemicals in the extracellular regions in the brain tissue.

项目总结/摘要因此，人们迫切需要一种新的传感技术，能够连续监测大脑中的神经化学物质，具有高时间分辨率的实时。虽然电活性神经递质（如如多巴胺和5-羟色胺）已经成功地使用高频伏安法（如快速- 扫描循环伏安法），非电活性物质（如谷氨酸盐）的测量仍然存在很大的困难。实现具有高时间分辨率的实时监测的挑战。该项目的目标是实现一个一种新的电化学传感平台，可以监测谷氨酸，一种众所周知的非电活性神经递质，具有生理相关的检测范围和高时间分辨率。拟议传感方法可以作为具有某些限制的酶传感或微透析的替代方案在时间分辨率和稳定性方面。部分受基于适体的电化学传感器的启发，所提出的传感机制利用新型合成目标受体作为目标识别单元信号转换器。谷氨酸受体由单链刺激响应模板聚合物形成与其模板分子谷氨酸特异性结合。此外，在选择性目标当聚合物被识别时，聚合物经历构象变化（从线性到折叠形状）。这种聚合物的变化形态可以通过使用附着在其上的氧化还原报告物（例如二茂铁）电化学检测聚合物。为了验证所提出的传感方法，将开发的传感器与两种成熟的方法，膜片钳和微透析技术。膜片钳系统是理想的然而，测量神经元突触间隙处化学交换的快速动力学（毫秒），缺乏化学特性。液相色谱-质谱联用微透析技术提供了特殊的化学特异性，然而，时间分辨率很差（分钟量级）。它预计开发的传感器平台将能够弥合这两种现有方法之间的差距并提供传感性能的多功能性。该项目的目标将通过以下方式实现：以下具体目的：（1）优化基于模板化聚合物的谷氨酸受体，以满足期望的性能指标;和（2）在生理环境中验证所开发的谷氨酸传感器。的该项目的成功成果将是开发一种新的通用平台技术，用于检测神经化学物质的实时时间分辨率足以研究突触通信以及用于监测脑组织细胞外区域的化学物质。