Scalable amperometric microchip array for high-throughput screening of small molecules, peptides or genetic perturbations for modulation of quantal transmitter release

可扩展的电流微芯片阵列，用于小分子、肽或遗传扰动的高通量筛选，以调节量子递质释放

• 批准号: 9201261
• 负责人: Manfred LINDAU
• 金额: $ 44.45万
• 依托单位: EXOCYTRONICS, LLC
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-18 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9201261
• 关键词: Adrenal Glands; Adverse drug effect; Amplifiers; Binding; Biological Assay; Botox; Brain; Catecholamines; Cell Count; Cells; ChIP-on-chip; Chromaffin Cells; Computer software; Cosmetics; Cytoplasmic Granules; Development; Devices; Dopamine; Drug Industry; Drug Modulation; Drug effect disorder; Electrodes; Ensure; Event; Exocytosis; Extracellular Space; Frequencies; Genetic; Goals; Hormones; Hour; Individual; Industry; Ion Channel; Kinetics; Levodopa; Measurement; Measures; Medical; Membrane; Methods; Microelectrodes; Microscopic; Molecular; Names; Neurobiology; Neurons; Neurotransmitters; Noise; Norepinephrine; Organelles; PC12 Cells; Parkinson Disease; Pattern; Peptides; Performance; Pharmaceutical Preparations; Pharmacology; Phase; Preclinical Drug Development; Process; Property; Proteins; Quality Control; Regulation; Research; Resolution; Semiconductors; Serotonin; Signal Transduction; Signaling Molecule; System; Technology; Testing; Time; Toxicology; Vesicle; Work; brain research; carbon fiber; commercialization; data acquisition; design; detector; dopaminergic neuron; drug development; drug discovery; drug testing; high throughput screening; innovation; innovative technologies; microchip; neurotransmitter release; novel; prototype; response; small molecule; tool; user-friendly; vesicular release

` The goal of this project is the development of a scalable n x m electrochemical detector array platform with on- chip amplifiers for massively parallel recordings of quantal transmitter release events. The neurobiological process that this assay analyzes is the process of exocytosis and transmitter release. Neurotransmitters and hormones are stored at high concentration in membrane-bound organelles. Upon stimulation, the contents of these vesicles are released in quantal events through a fusion pore that connects the vesicular lumen to the extracellular space. In the treatment of Parkinson's disease the drug levodopa increases dopamine release from the reduced number of dopaminergic neurons. On the other hand, BoTox treatment acts by reducing transmitter release. In addition to these examples, many other drugs and many molecular manipulations modulate transmitter release in various ways. This regulation of transmitter release occurs not only via changing the number or frequency of quantal release events but also via modulation of quantal size and of the kinetics of release from individual vesicles. The technology developed in this project is adapted from the semiconductor industry and involves a CMOS microelectronic chip for on-chip recordings of single quantal release events of oxidizable transmitter molecules such as noradrenaline, dopamine, or serotonin. The technology will allow the simultaneous recording of single vesicle release events from hundreds of cells without the need for microscopic observation and manipulation, and thereby provides a high-throughput platform to characterize molecular and pharmacological manipulations. This technology will be a very important tool for preclinical drug development studies, including pharmacology, efficacy and toxicology and provide a pipeline for target identification and drug discovery. It will also considerably accelerate research towards understanding vesicular release mechanisms and their modulation by drugs and genetic factors.

` 该项目的目标是开发一个可扩展的n x m电化学检测器阵列平台， 用于量子发射器释放事件的大规模并行记录的芯片放大器。的神经生物学 该测定分析的过程是胞吐和递质释放的过程。神经递质和 激素以高浓度储存在膜结合的细胞器中。在刺激下， 这些囊泡在量子事件中通过连接囊泡腔和囊泡的融合孔释放， 细胞外间隙在帕金森氏症的治疗药物左旋多巴增加多巴胺的释放 多巴胺能神经元数量的减少另一方面，BoTox治疗通过减少 发射器释放除了这些例子，许多其他药物和许多分子操作 以各种方式调节发射器释放。变送器释放的这种调节不仅通过 改变量子释放事件的数量或频率，而且还通过调制量子大小和 从单个囊泡释放的动力学。该项目开发的技术是从 半导体工业中的一种，涉及一种用于单量子的片上记录的CMOS微电子芯片， 释放事件的可氧化的递质分子，如去甲肾上腺素，多巴胺，或血清素。的 这项技术将允许同时记录来自数百个细胞的单个囊泡释放事件， 需要显微镜观察和操作，从而提供了一个高通量平台， 表征分子和药理学操作。这项技术将是一个非常重要的工具， 临床前药物开发研究，包括药理学，疗效和毒理学，并提供了一个管道的目标 鉴定和药物发现。这也将大大加快研究，以了解囊泡 释放机制及其通过药物和遗传因素的调节。