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

` 本项目的目标是开发一种可扩展的n×m电化学检测器阵列平台，该平台具有以下功能： 用于大规模并行记录量子发射机释放事件的芯片放大器。神经生物学 本实验分析的过程是胞吐和递质释放的过程。神经递质和 激素以较高的浓度储存在膜结合细胞器中。在刺激下，内容物 这些囊泡在量子事件中通过连接囊泡管腔和 细胞外空间。在帕金森病的治疗中，药物左旋多巴增加了多巴胺的释放 由于多巴胺能神经元数量的减少。另一方面，肉毒杆菌治疗通过减少 发射机释放。除了这些例子，许多其他药物和许多分子操作 以各种方式调制发射机释放。这种对递质释放的调节不仅通过 改变量子释放事件的数量或频率，但也通过调制量子大小和 从单个囊泡释放的动力学。本项目开发的技术改编自 半导体工业，涉及用于单量子数片上记录的CMOS微电子芯片 可氧化递质分子的释放事件，如去甲肾上腺素、多巴胺或5-羟色胺。这个 该技术将允许同时记录数百个细胞的单个囊泡释放事件，而不需要 需要进行微观观察和操纵，从而提供了一个高通量平台 描述分子和药理操作的特征。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，并为靶向提供管道 鉴定和药物发现。这也将大大加快对水泡的研究。 释放机制及其药物和遗传因素的调节。

` 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.