NeuroPredict, A screening assay for chemicals that affect the differentiation of human neural cells.

ABSTRACT A growing human health concern is that exposure to chemicals in our environment harms the highly vulnerable period of human brain developmentIndeedincreasing evidence shows that even simpleacute exposures of the developing brain to select agents cause profound neurological disorders such as epilepsyautism and intellectual disabilityDespite this vulnerabilitythe reliablehigh throughput identification of neurotoxins that affect this process has been laggingMajor hurdles include the time and cost required for these assays when using animal modelsthe difficulty of relating rodent data to human brain developmentand the difficulty in generating easy to interpret metrics for how a chemical affects the multiple cell types required for proper neurodevelopmentNzumbe Increceived a Phase I grant to address these challengesOur work established and validated awellhigh content assay that determines whether a chemical affects neural differentiationWe identified discrete timepoints and cell specific markers that can be used to screen for aberrant changes in neural differentiation following exposures to chemicalsWe are now seeking Phase II SBIR funding in response to RFA ESNovel Assays for Screening the Effects of Chemical Toxicants on Cell DifferentiationOur plans under Phase II are to further innovate and deliver a more rapidpredictive testcalled NeuroPredictTMwhich would greatly reduce cost and give simpleeasy to interpret metrics to determine how a chemical affects neural differentiationOur first Aim is to create specially engineered human iPSC derived neural progenitor cellshNPCsthat express reporter proteins that identify the basic cell types that arise during neural differentiationThese reporter proteins can be assayed at multiple time points during the differentiation processThe ratio of these different reporter proteins will represent the relative proportion of the basic cells type present during neural differentiationhNPCglial cellsand neuronsThusa toxic effect of chemical exposure on the differentiation process will be reflected by changes in the reporter protein outputsThe second Aim is to use the NeuroPredictTM assay to classify the early functional and disease associated effects of known neurotoxins on neural differentiationThis strategy will provide data for a short term assay that can quickly classify chemicals with unknown neurotoxic effects PROJECT NARRATIVE The period of active neural differentiation is particularly sensitive to chemical exposuresHoweverin vitro screening assays to detect chemical perturbations of the neural differentiation process are lackingThe objective of this application is to build on our Phase I proof of concept work and commercialize NeuroPredictTMa low costeasily scalable screening assay to identify chemicals that perturb neural differentiation