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: 8828797
• 负责人: John D. Houle
• 金额: $ 127.19万
• 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 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8828797
• 关键词: Acute; Address; Animal Model; Axon; Brain Stem; Cell Therapy; Cell Transplantation; Cerebrum; Chronic; Communication; Data; 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; collaborative environment; efficacy testing; functional restoration; improved; injured; neurotransmission; 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.

申请人描述：轴突在神经系统中提供远程通信。受损脊髓轴突的再生带来了将尾侧脊髓与吻侧脑干和大脑重新连接并恢复感觉和运动功能的潜力。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结合多种修复机制时。本项目提出的研究将探讨脊髓损伤干预中改善功能恢复的细胞内机制，重点关注轴突间室中的新相互作用。我们将验证一个假设，即受损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，这些信号事件集中在局部蛋白质合成机制上，这有助于轴突的生长和成熟。我们将通过两个具体目标来验证这一假设，即将主要研究者在轴突生长和轴突内信号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以及项目II （Fischer）在祖细胞方面的专业知识结合起来