Spinal cord injury, plasticity and transplant mediated repair

申请人提供的描述：轴突在神经系统中提供远程通讯。损伤脊髓中轴突的再生带来了将尾部脊髓重新连接到吻侧脑干和大脑的可能性，并恢复了感觉和运动功能。神经修复领域取得了重大进展，有望恢复脊髓损伤的功能，特别是当干预措施可以组合起来针对多种修复机制时。本项目中提出的研究将探索脊髓损伤干预措施中促进功能恢复的细胞内机制，重点是轴突间的新的相互作用。我们将验证这一假设，即损伤脊髓的微环境和旨在克服抑制微环境的干预措施可以调节轴突内信号事件，这些信号事件会聚在局部的蛋白质合成机制上，这有助于轴突的生长和成熟。我们将用两个特定的目标来检验这一假设，这两个目标是将主要研究者在轴突生长和轴突内信号传递方面的专业知识与项目III(Houle)在脊髓损伤再生治疗方面的专业知识和项目II(Fischer)在先祖方面的专业知识结合在一起 脊髓损伤的细胞疗法。这个项目的第一个目的是询问运动/训练区域是否通过转录后机制调节轴突生长潜力，这些区域已经被证明可以促进脊髓损伤的恢复。将使用原代神经元培养和周围神经移植到横断的脊髓来测试整体和轴突内的翻译控制机制。第二个目的是询问用于脊髓损伤的前体细胞是否可以直接调节轴突内信号，通过轴突mRNA运输和翻译控制机制来调节轴突的内在生长潜力和成熟。我们将把这些数据与项目II整合，以解决宿主轴突与脊髓损伤中移植的前体细胞相互作用时的mRNA翻译问题。这些实验的总体目标是揭示促进轴突生长和信号传递的机制，这些机制可用于合理微调未来的神经修复策略。 相关性：轴突有能力产生再生所需的自己的蛋白质，但尚不清楚这是否发生在脊髓中，或者是否为脊髓损伤开发的神经修复策略针对这种轴突内信号机制。我们将确定支持脊髓再生的生长环境和能够改善功能恢复的训练方案如何影响轴突信号转导和轴突再生。

Description as provided by applicant: Axons provide long-range communication in the nervous system. Regeneration of axons in the injured spinal cord brings the potential to reconnect the caudal spinal cord to rostral brain stem and cerebrum and restore sensory and motor function. Significant advances have been made in the field of neural repair that hold promise for restoring function in spinal cord injury, particularly when interventions can be combined to target multiple repair mechanisms. The studies proposed in this project will explore the intracellular mechanisms underlying improved functional recovery in spinal cord injury interventions, focusing on novel interactions in the axonal compartment. We will test the hypothesis that the microenvironment of the injured spinal cord and interventions aimed at overcoming the inhibitory microenvironment can modulate intraaxonal signaling events that converge on the local protein synthesis machinery and this contributes to axonal growth and maturation. We will test this hypothesis with two specific aims that bring together expertise of the principal investigator in axonal growth and intra-axonal signaling with expertise from Project III (Houle) in regenerative therapies for spinal cord injury and Project II (Fischer) in progenitor cell therapies for spinal cord injury. The first aim of this project asks if exercise/training regiens that have been shown to improve recovery from spinal cord injury regulate axonal growth potential through post-transcriptional mechanisms. Both overall and intra-axonal translational control mechanisms will be tested using primary neuronal cultures and peripheral nerve grafting into the transected spinal cord. The second aim will ask if precursor cells used for spinal cord injury can directly modulate intra-axonal signaling to regulate the intrinsic growth potential and maturation of axons through axonal mRNA transport and translational control mechanisms. We will integrate these data with Project II to address mRNA translation in host axons as they interact with grafted precursor cells in SCI. The overall objective of these experiments is to uncover mechanisms underlying enhanced axonal growth and signaling that can be used to rationally fine tune future neural repair strategies. RELEVANCE: Axons have the ability to generate their own proteins needed for regeneration, but it is not clear if this occurs in the spinal cord or if neural repair strategies developed for spinal cord injury target this intra-axonal signaling mechanism. We will determine how growth supportive environments for spinal cord regeneration and training regimens that can improve functional recovery impact on axonal signal transduction and axon regrowth.