The contraction of skeletal muscle is induced by neurotransmitter release at neuromuscular junctions (NMJs), where motor neurons innervate myofibers. Studies of NMJ formation/function were mostly confined to mouse models or heterologous 2D primary cell co-cultures. We aim to elucidate mechanisms underlying human muscle-nerve connectivity in health and disease by investigating how muscle-derived factors regulate NMJ homeostasis in human-relevant microphysiological 3D models. We have integrated our well-established expertise in human pluripotent stem cells, CRISPR-based tools, optogenetics, microfabrication and systems biology to overcome current technical challenges. This project will have a significant impact on understanding human muscle-nerve crosstalk, and reducing/replacing research animals.
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