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.

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