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

具有再生能力的生物体中脊髓生长和修复的三维模型

• 批准号: 1538505
• 负责人: Gunther Zupanc
• 金额: $ 38.9万
• 依托单位: Northeastern University
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1538505&HistoricalAwards=false
• 关键词: Three; dimensional; Model; Spinal; Cord

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.

脊髓损伤代表了一种无法治愈的疾病，通常会导致人类严重的终身残疾。迄今为止，为改善结构再生而制定的许多治疗策略仅导致了适度的改进。对生物体的研究提供了一种替代策略，这些生物可以在受伤后自发再生中枢神经组织，例如鱼和sal。了解这种物种中脊髓愈合的生物学机制为鉴定治疗人类脊髓损伤的治疗靶标提供了新的翻译机会。该项目重点介绍了一种示例性生物，即棕色幽灵刀鱼apteronotus leptorhynchus。目的是通过数学和计算建模将现有实验数据的财富整合到系统级理论框架中。所得模型将用于发现有关正常脊髓生长的一些规则，并确定结构和功能性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。从生物学的角度研究了脊髓组织生长及其再生的基础的细胞和分子过程。但是，很少有人尝试通过计算和/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，将通过使用刀鱼apteronotus leptorhynchus作为脊髓损伤后能够自发再生的生物之一开发这种模型。将采用一种混合，离散的方法，将基于代理的框架与分子水平的动态系统框架相结合。这项研究将导致可能成为竞争能力的生物中生长和修复的细胞和分子现象的第一个计算模型的发展。这将导致对中枢神经系统内的康复动态的全面理解，从而定义最佳再生条件。作为该项目的一部分建立的计算框架将为其他从事增长和再生机制的研究人员提供扩展的机会，包括制定治疗脊髓损伤的治疗策略。