High-throughput Hazard,Dose-responseandPopulationVariabilityAssessmentofCardiotoxicity in aHumanInducedPluripotentStem Cell(iPSC)-derivedinvitro Culture Model
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abstract
The long-term objective of the Center is to advance chemical risk assessment by establishing and validating effective, accurate and fiscally responsible means for identifying/characterizing cardiac chemical hazards. Recent advances in stem cell research and establishment of robust protocols for culturing, distribution and phenotyping holds promise for development of a functional cardiac OCM for modeling cardiovascular disease and testing for chemical hazards. The central hypotheses of this proposal are that: (i) stem cell-derived cardiomyocyte cultures constitute an effective organotypic culture model for predictive toxicity screening of environmental chemicals; (ii) a population-based experimental design utilizing a panel of human iPSCs and mouse Collaborative Cross (CC) can assess variation in toxicity to better characterize uncertainties; and (iii) integration of dosimetry with screening provides an in vivo context to in vitro data and improves human health assessments. Project 1 will conduct population-based concentration-response high-content/-throughput in vitro screening of up to 200 ToxCast chemicals in iPSC-derived cardiomyocytes from 100 humans, and will collect pharmacokinetic data using hepatocytes..........
