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ICCVAM Biennial Report 2018-2019

ICCVAM Biennial Report 2018-2019
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https://ntp.niehs.nih.gov/go/891773

Human Stem Cell Neuronal Platform with Phenotypic and Physiological Output

The Biological Modeling Group of the AFRL 711th Human Performance Wing in collaboration with the Sanford Burnham Prebys Medical Discovery Institute is developing a human in vitro stem cell assay system to determine the mechanism of neurotoxins that potentially affect human brain function. This research includes benchmark testing of over 200 neurotoxins with known mechanisms. Effects on treated cells are assessed by neurophysiology (multi-electrode array), mitochondrial membrane potential changes, and reactive oxygen species generated in the cell culture system. The results of these ongoing studies are being analyzed to develop predictive toxicology capabilities using QSAR analysis and read-across computational methods. These approaches will enable predictions of toxicity of unknown chemicals with varying degrees of confidence, depending on how similar the unknown chemicals are to chemicals in the known database. The next phase of human neuron stem cell readout will involve a mechanistic large-scale neural network modeling of chemically induced changes in the in vitro firing activity of the networking neurons. By measuring these changes in networking firing rates in combination with behavior phenotypes in the case of known chemical entities, the goal is to be able to predict the response for unknown chemicals or chemicals with limited experimental data.

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