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信。损伤脊髓中轴突的再生带来了将尾侧脊髓与喙侧脑干和大脑重新连接并恢复感觉和运动功能的可能性。在神经修复领域已经取得了重大进展，有望恢复脊髓损伤的功能，特别是当干预措施可以结合以靶向多种修复机制时。本项目中提出的研究将探索脊髓损伤干预中改善功能恢复的细胞内机制，重点是轴突隔室中的新型相互作用。我们将测试这一假设，即损伤脊髓的微环境和旨在克服抑制性微环境的干预措施可以调节轴突内信号传导事件，这些事件聚集在局部蛋白质合成机制上，这有助于轴突生长和成熟。我们将通过两个特定的目标来测试这一假设，这两个目标将主要研究者在轴突生长和轴突内信号传导方面的专业知识与脊髓损伤再生疗法项目III（Houle）和祖细胞再生疗法项目II（Fischer）的专业知识结合起来。 脊髓损伤的细胞疗法该项目的第一个目的是询问已被证明可以改善脊髓损伤恢复的运动/训练区域是否通过转录后机制调节轴突生长潜力。将使用原代神经元培养物和周围神经移植到横断脊髓中来测试整体和轴突内平移控制机制。第二个目标将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传导，以通过轴突mRNA转运和翻译控制机制来调节轴突的内在生长潜力和成熟。我们将整合这些数据与项目II，以解决宿主轴突中的mRNA翻译，因为它们与SCI中移植的前体细胞相互作用。这些实验的总体目标是揭示增强轴突生长和信号传导的潜在机制，这些机制可用于合理地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蛋白质，但目前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靶向这种轴突内信号传导机制。我们将确定脊髓再生的生长支持环境和可以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.