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

脊髓损伤是一种无法治愈的疾病，通常会导致严重的终身残疾。迄今为止开发的许多用于改善结构再生的治疗策略仅导致适度的改善。另一种策略是通过研究可以在损伤后自发再生中枢神经组织的生物体，如鱼类和蝾螈。了解这些物种脊髓愈合的生物学机制为确定治疗人类脊髓损伤的治疗靶点提供了新的转化机会。该项目的重点是一个典型的生物体，棕色鬼刀鱼Apteronotus leptorhynchus的理论研究。我们的目标是通过数学和计算建模，将丰富的现有实验数据整合到系统级的理论框架中。由此产生的模型将被用来揭示一些规则正常的脊髓生长，以及确定结构和功能的脊髓再生的最佳条件。此外，该项目将展示跨学科方法的力量，特别是使用工程师和数学家开发的工具来解决生物学问题。从生物学角度对脊髓组织生长及其损伤后再生的细胞和分子过程进行了广泛的研究。然而，很少有人试图通过计算和/或数学建模将所得的经验数据整合到一个全面的理论框架中。作为该项目的一部分，将使用刀鱼Apteronotus leptorhynchus作为脊髓损伤后能够自发再生的最佳检查生物之一来开发这样的模型。一个混合的，离散连续的方法将被采用，结合在细胞水平的动态系统框架在分子水平上的一个基于代理的框架。这项研究将导致什么可能是第一个计算模型的细胞和分子现象的基础上的生长和修复再生能力的生物体的发展。它将导致对中枢神经系统内愈合动力学的全面了解，从而有可能确定最佳再生的条件。作为该项目的一部分建立的计算框架将为其他研究生长和再生机制的研究人员提供更多的机会，包括开发治疗脊髓损伤的治疗策略。

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.