Spinal cord injury, plasticity and transplant mediated repair

脊髓损伤、可塑性和移植介导的修复

• 批准号: 8652507
• 负责人: John D. Houle
• 金额: $ 125.92万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-06-15 至 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652507
• 关键词: Acute; Address; Animal Model; Axon; Brain Stem; Cell Therapy; Cell Transplantation; Cerebrum; Chronic; Communication; Data; Environment; Event; Exercise; Felis catus; Fostering; Future; Genetic Translation; Growth; Injury; Instruction; Intervention; Mediating; Messenger RNA; Motor; Natural regeneration; Nervous system structure; Neurons; Patients; Peripheral Nerves; Physical Rehabilitation; Principal Investigator; Protein Biosynthesis; Proteins; Recovery; Recovery of Function; Regimen; Sensory; Signal Transduction; Spinal Cord; Spinal cord injury; Stem cells; Testing; Tissue Transplantation; Training; Transplantation; axon growth; axon regeneration; clinically relevant; efficacy testing; functional restoration; improved; injured; novel; preclinical study; precursor cell; regenerative therapy; relating to nervous system; repaired; research study; spinal cord regeneration

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.

申请人提供的描述：轴突在神经系统中提供远距离通信。受伤脊髓中轴突的再生有可能将尾部脊髓与头端脑干和大脑重新连接起来，并恢复感觉和运动功能。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，特别是当可以结合干预措施来针对多种修复机制时。该项目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，重点关注轴突室中的新相互作用。我们将测试以下假设：受损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汇聚于局部蛋白质合成机制的轴突内信号事件，这有助于轴突生长和成熟。我们将通过两个具体目标来检验这一假设，将主要研究者在轴突生长和轴突内信号转导方面的专业知识与项目 III (Houle) 在脊髓损伤再生疗法和项目 II (Fischer) 在祖细胞方面的专业知识结合起来。 脊髓损伤的细胞疗法。该项目的第一个目标是询问已被证明可以改善脊髓损伤恢复的运动/训练方案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将周围神经移植到横断的脊髓中来测试整体和平移控制机制。第二个目标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传导，从而通过轴突 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。我们将这些数据与 Project II 整合，以解决宿主轴突与 SCI 中移植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增强轴突生长和信号传导的机制，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自身蛋白质，但尚不清楚这种情况是否发生在脊髓中，或者针对脊髓损伤开发的神经修复策略是否针对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。