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长距离通信。受伤的脊髓中轴突的再生带来了将尾脊髓重新连接到鼻脑干和大脑以及恢复感觉和运动功能的潜力。在神经修复领域已经取得了重大进展，这有望恢复脊髓损伤的功能，尤其是当可以将干预措施组合起来以靶向多种修复机制时。该项目中提出的研究将探讨脊髓损伤干预措施中功能恢复的基础内机制，重点是轴突隔室中的新型相互作用。我们将检验以下假设：旨在克服抑制性微环境的受伤的脊髓和干预措施的微环境可以调节递增局部蛋白质合成机械及其有助于轴突生长和成熟的局部信号事件。我们将以两个具体的目的来检验这一假设，以将主要研究者的轴突生长和轴内信号传导的专业知识汇总在一起，并具有来自Project III（Houle）的专业知识（Houle）的脊髓损伤再生疗法（fischer）的祖细胞（Fischer）的专业知识。 脊髓损伤的细胞疗法。该项目的第一个目标询问是否已证明已经通过转录后机制来改善脊髓损伤的恢复能够改善轴突生长潜力。总体和轴内翻译控制机制都将使用原发性神经元培养物和外周神经接枝到跨脊髓中进行测试。第二个目的将询问用于脊髓损伤的前体细胞是否可以直接调节轴内信号传导，以通过轴突mRNA传输和翻译控制机制来调节轴突的内在生长潜力和成熟。我们将将这些数据与项目II集成在一起，以解决宿主轴突中与SCI中移植的前体细胞相互作用时的mRNA翻译。这些实验的总体目的是发现轴突生长和信号的基础机制，可用于合理调整未来的神经修复策略。 相关性：轴突具有生成再生所需的蛋白质的能力，但是尚不清楚这是否发生在脊髓中，或者是为脊髓损伤而开发的神经修复策略的目标。我们将确定脊髓再生和训练方案的生长支持环境如何改善功能恢复对轴突信号转导和轴突再生的影响。