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

基本信息

批准号：
9334939
负责人：
Manfred LINDAU
金额：
$ 42.42万
依托单位：
EXOCYTRONICS, LLC
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-08-18 至 2021-07-31
项目状态：
已结题

项目摘要

` 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 电化学探测器阵列平台，用于大规模并行记录量子发射器释放事件的芯片放大器。神经生物学本测定分析的过程是胞吐作用和递质释放的过程。神经递质和激素以高浓度储存在膜结合细胞器中。受到刺激后，其内容物这些囊泡在量子事件中通过连接囊泡腔和细胞外空间。在治疗帕金森病时，药物左旋多巴会增加多巴胺的释放来自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。除了这些例子之外，还有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。发射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，还可以通过调制量子大小和单个囊泡释放的动力学。该项目开发的技术改编自半导体行业，涉及用于单量子片上记录的 CMOS 微电子芯片可氧化递质分子（如去甲肾上腺素、多巴胺或血清素）的释放事件。这技术将允许同时记录数百个细胞的单个囊泡释放事件，而无需显微观察和操作的需要，从而提供了一个高通量平台表征分子和药理学操作。这项技术将成为一个非常重要的工具临床前药物开发研究，包括药理学、功效和毒理学，并为靶点提供管道鉴定和药物发现。它还将大大加速了解囊泡的研究释放机制及其药物和遗传因素的调节。