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: 9252539
• 负责人: Itzhak Fischer
• 金额: $ 20.78万
• 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/9252539
• 关键词: Acute; Address; Adult; Alkaline Phosphatase; Area; Axon; Behavioral; Brain Injuries; Brain Stem; Cell Nucleus; Chondroitinases; Chronic; Cicatrix; Deafferentation procedure; Development; Electric Stimulation; Electrophysiology (science); Embryo; Environment; Evoked Potentials; Exercise; Experimental Designs; FOS gene; GRP gene; Gene Expression; Growth; Individual; Injury; Lentivirus Vector; Lesion; Mediating; Modeling; Natural regeneration; Neurodegenerative Disorders; Neurons; Physiological; Property; Protocols documentation; Quality of life; Rattus; Recovery; Role; Sensory; Site; Societies; Spinal cord injury; 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; exercise training; experimental study; functional improvement; functional restoration; improved; improved functioning; in vivo; nerve stem cell; neuronal replacement; neurotrophic factor; neurotropin; novel; permissiveness; postsynaptic; progenitor; protein biomarkers; repaired; 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.

尽管在阐明神经干细胞特性和将其用于移植方面取得了进展，但挑战