Scalable amperometric microchip array for high throughput screening of small molecules peptides or genetic perturbations for modulation of quantal transmitter 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 Parkinsonandapos 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 ` Release of neurotransmitters and hormones is regulated by many proteins signaling molecules and various drugs Two examples are the drug L Dopa used to treat Parkinsonandapos s disease or the cosmetic BoTox treatment The goal of this project is to provide a scalable n x n electrochemical detector array platform with on chip amplifiers for massively parallel recordings of individual transmitter release events This novel microchip array platform will be an important tool for preclinical drug development studies including pharmacology efficacy and toxicology and provide a pipeline for target identification and drug discovery