A Three-dimensional Model of Spinal Cord Growth and Repair in a Regeneration-competent Organism

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Spinal cord injury represents an incurable condition, usually leading to severe life-long disability in humans. Numerous therapeutic strategies developed thus far to improve structural regeneration have resulted in only modest improvements. An alternative strategy is provided by the study of organisms that can spontaneously regenerate central nervous tissue after injury, such as fish and salamanders. Understanding the biological mechanisms underlying spinal cord healing in such species provides novel translational opportunities for the identification of therapeutic targets to treat spinal cord injuries in humans. This project focuses on the theoretical study of one exemplary organism, the brown ghost knifefish Apteronotus leptorhynchus. The goal is to integrate the wealth of existing experimental data into a systems-level theoretical framework through mathematical and computational modeling. The resulting model will be used to uncover some of the rules governing normal spinal cord growth, as well as to determine the optimal conditions for structural and functional spinal cord regeneration. Moreover, this project will demonstrate the power of interdisciplinary approaches, in particular the use of tools developed by engineers and mathematicians for solving biological problems. The cellular and molecular processes underlying the growth of spinal cord tissue and its regeneration after injury have been studied extensively from a biological perspective. However, few attempts have been made to integrate the resulting empirical data into a comprehensive theoretical framework through computational and/or mathematical modeling. As part of this project, such a model will be developed by using the knifefish Apteronotus leptorhynchus as one of the best-examined organisms capable of spontaneous regeneration after spinal cord injury. A hybrid, discrete-continuous approach will be employed, combining an agent-based framework at the cellular level with a dynamical systems framework at the molecular level. This study will lead to the development of what is likely to be the first computational model of the cellular and molecular phenomena underlying growth and repair in a regeneration-competent organism. It will lead to a comprehensive understanding of healing dynamics within the central nervous system, making it possible to define the conditions for optimal regeneration. The computational framework established as part of the project will provide extended opportunities for other researchers working on growth and regeneration mechanisms, including the development of therapeutic strategies for the treatment of spinal cord injuries.