"Investigating the link between patient genotype and neurotrauma tolerance using human induced pluripotent stem cells"
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Abstract: Defining the mechanical tolerance of the human central nervous system in trauma events is a grand challenge in injury biomechanics. Decades of effort have brought steady progress in quantifying how the body is loaded during a neurotrauma event and relating those loads to tissue deformation. Nevertheless, clear, precise, universally applicable thresholds for injury remain elusive. Observational studies frequently report a handful of poor clinical outcomes among subjects experiencing modest loading while many other subjects experience equal or worse loading with good clinical outcomes. These data suggest that neurotrauma tolerance is subject specific. Factors that may influence neurotrauma tolerance for a particular subject include age, sex, head dimensions, neck strength, brain morphology, and several others. Our goal is to understand the role of genetics in subject-specific neurotrauma tolerance. Human in vitro models have a unique capacity to address this question. Human induced pluripotent stem cells (hiPSCs) can be generated from human donors and used to generate brain cells that retain the genetic identity of the donor. What is more, their genomes can be edited one gene at a time. Therefore, experiments with hiPSCs can definitively relate a particular genetic variant to a change in outcome. We have designed and built a suite of tools to mechanically traumatize human brain cell cultures derived from hiPSCs and measure their health and activity. We have used these tools to demonstrate that post-traumatic pathology is more severe when mutations associated with neurodegeneration are present. This talk will describe these efforts and discuss the potential of human in vitro models to reveal the role of genotype in neurotrauma tolerance.
Bio: John Finan is an Assistant Professor in the Department of Mechanical and Industrial Engineering at the University of Illinois at Chicago. He studies the biomechanics of the human brain, particularly as it relates to understanding and treating traumatic brain injuries and their long-term consequences. He uses human brain cells and organoids (self-organizing aggregates of thousands of brain cells) derived from stem cells in his research because they allow him to answer questions about how human brains differ from animal brains, and why one human’s brain differs from another’s. He received his PhD. from Duke University, where he published on improving motorcycle helmets and the biomechanics of cartilage. He also held a post-doctoral appointment at Columbia University in New York, where he studied the biomechanics of the rat, pig, and human brains and worked on a novel approach to treating brain swelling after trauma. His work has been funded by the National Institutes of Health and the National Science Foundation.
Host: Jason Forman