Applications of Neural Stem Cells in Spinal Cord Injury

神经干细胞在脊髓损伤中的应用

• 批准号: 8534981
• 负责人: Itzhak Fischer
• 金额: $ 26.21万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/8534981
• 关键词: Acute; Address; Adult; Alkaline Phosphatase; Area; Axon; Behavioral; Brain Injuries; Brain Stem; Cell Nucleus; Chondroitinases; Chronic; Cicatrix; Deafferentation procedure; Degenerative Disorder; Development; Electric Stimulation; Electrophysiology (science); Embryo; Environment; Evoked Potentials; Exercise; Experimental Designs; FOS gene; GRP gene; Gene Expression; Growth; Hyaluronidase; Individual; Injury; Instruction; Lentivirus Vector; Lesion; Mediating; Modeling; Natural regeneration; Neurodegenerative Disorders; Neurons; Physiological; Principal Investigator; Property; Proteins; Protocols documentation; Quality of life; Rattus; Recovery; Role; Sensory; Site; Societies; Spinal cord injury; Staging; Synapses; System; Testing; Time; Training; Transgenic Organisms; Translating; Transplantation; Viral Vector; adeno-associated viral vector; axon growth; axon regeneration; central nervous system injury; density; design; dorsal column; functional improvement; functional restoration; improved; improved functioning; in vivo; nerve stem cell; neuronal replacement; neurotrophic factor; novel; postsynaptic; progenitor; programs; repaired; research study; restoration; sensory system; stem cell biology; synaptogenesis; tool; vector

Despite progress in elucidating neural stem cell properties and using them for transplantation, the challenges of neuronal cell replacement following CNS injury remain difficult to resolve. This proposal will use transplants of neuronal and glial restricted progenitors (NRP/GRP) to reconnect the disrupted sensory system after acute and chronic spinal cord injury (SCI). The experiments are designed to build neuronal relays across a dorsal column lesion reconnecting the denervated dorsal column nucleus (DCN). The proposal addresses important issues related to application of stem cell biology to CNS injury, including how to generate graft derived neurons, direct their axon growth, overcome the inhibitory environment of the injury, and, most importantiy, how to form functional synapses with the denervated target. We will continue our studies that demonstrated the principles of relay formation with NRP/GRP transplants by testing specific hypotheses for improving the functional aspects of the relay and advance this strategy to chronic SCI. In Aim 1, we will test the role of synaptic density and activity-induced plasticity in producing stable and functional synaptic connections at the DCN target. We propose that a) synaptic activity with target neurons will improve through summation of the evoked potentials at the target site by increasing synaptic density (more axons) and reducing inhibition of perineuronal nets at the DCN, and b) synapse stability will improve with time, with task-specific activity, and with stimulation of the sensory relay. In Aim 2 we will test the hypothesis that denervated targets can be reconnected and retrained to correctly interpret sensory information at a chronic injury stage. Specifically, we will test a) how to promote host sensory axons to grow into the site of a chronic injury, and b) how to promote connectivity at the target, where the DCN has been subject to prolonged deafferentation. To achieve connectivity in the chronic injury, we will use neurotrophins, chondroitinase (delivered by novel viral vectors), and exercise/training protocols. This relay model allows us to go beyond the current focus on regeneration, exploit the advantages of embryonic neurons produced by neural stem cells, and examine the steps needed to restore connectivity and improve function in a well-defined system. RELEVANCE (See instructions): Spinal cord injury has devastating effects on quality of life accompanied by a heavy financial burden to individuals and society. This proposal addresses potential therapies for spinal cord injury using transplants of neural stem cells to restore connectivity and function. The strategies developed in this project are also relevant to brain injury and other neuro-degenerative disorders that require neuronal cell replacement

尽管阐明神经干细胞特性并将其用于移植方面取得了进展，但仍有挑战 中枢神经系统损伤后的神经元细胞置换量仍然难以解决。该建议将使用 神经元和神经胶质限制祖细胞（NRP/GRP）的移植以重新连接破坏的感觉 急性和慢性脊髓损伤（SCI）后的系统。实验旨在构建神经元 在背侧柱病变上的继电器重新连接了无法进行的背柱​​核（DCN）。这 提案解决了与将干细胞生物学应用于中枢神经系统损伤的应用有关的重要问题，包括 为了产生移植神经元，指导其轴突生长，克服损伤的抑制环境， 而且，最重要的是，如何与未经许可的目标形成功能突触。我们将继续我们的 研究表明通过测试特定的NRP/GRP移植的继电器形成原理 假设改善继电器的功能方面并将这一策略推向慢性SCI。目标 1，我们将测试突触密度和活性诱导的可塑性在产生稳定和功能的作用 DCN目标处的突触连接。我们建议a）具有靶神经元的突触活动将改善 通过增加突触密度（更多轴突），通过求和目标位点的诱发电势 并减少DCN的抑制会内神经元网，b）突触稳定性会随着时间的流逝而提高，随着时间的流逝 特定于任务的活动，并刺激感觉继电器。在AIM 2中，我们将检验以下假设 可以重新连接而死的目标，以正确解释慢性的感觉信息 伤害阶段。具体而言，我们将测试a）如何促进宿主感觉轴突生长到慢性的位置 伤害，b）如何在目标延长的目标上促进目标的连通性 停用。为了实现慢性损伤的连通性，我们将使用神经营养蛋白，软骨素酶 （由新型病毒载体提供）和运动/训练方案。这种继电器模型使我们能够超越 当前对再生的关注，利用神经茎产生的胚胎神经元的优势 细胞，并检查恢复连通性并改善定义明确的系统功能所需的步骤。 相关性（请参阅说明）： 脊髓损伤对生活质量产生毁灭性影响，伴随着沉重的财务负担 个人和社会。该提案解决了使用移植的潜在疗法 神经干细胞以恢复连通性和功能。该项目中制定的策略也是 与需要神经元细胞置换的脑损伤和其他神经差异疾病有关