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: 7796575
• 负责人: Itzhak Fischer
• 金额: $ 27.93万
• 依托单位: DREXEL UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7796575
• 关键词: Ablation; Adult; Affect; Animals; Antibodies; Area; Astrocytes; Axon; Behavior; Behavioral; Brain-Derived Neurotrophic Factor; CSPG3 gene; Cell Differentiation process; Cell Maturation; Cell Survival; Cells; Characteristics; Chest; Chondroitin Sulfate Proteoglycan; Cicatrix; Collagen; Consult; Control Groups; Contusions; Core Facility; Core Protein; Corticospinal Tracts; Data; Databases; Deposition; Development; Dissection; Elements; Embryo; Environment; Event; Experimental Designs; Fibroblast Growth Factor 2; Freezing; GAG Gene; GDNF gene; GRP gene; Gait; Gene Expression; Gene Expression Profile; Generations; Genes; Glial Fibrillary Acidic Protein; Gray unit of radiation dose; Growth; Growth Factor; Hindlimb; Histocytochemistry; Histology; Hypersensitivity; Image Analysis; Immune response; Inflammation; Injury; Integrins; Intervention; Laminin; Lasers; Lateral; Lesion; Light; Link; Locomotion; Measurement; Measures; Mechanical Stimulation; Mediating; Microdissection; Microglia; Modeling; Molecular Profiling; Motor; Myelin Basic Proteins; Natural regeneration; Neuroglia; Neuronal Differentiation; Neurons; Nuclear Pore Complex; Oligodendroglia; Pattern; Phenotype; Physiological; Polymerase Chain Reaction; Preparation; Procedures; Process; Production; Property; Protocols documentation; Publishing; Rattus; Reaction; Recovery; Recovery of Function; Relative (related person); Role; Safety; Sampling; Schwann Cells; Sensory; Series; Serotonin; Side; Signal Transduction; Site; Somatomedins; Spinal; Spinal Cord; Spinal cord injury; Sprague-Dawley Rats; Staging; Staining method; Stains; Statistical Methods; Stimulus; Structure of rubrospinal tract; Suspension substance; Suspensions; Synapses; Synaptophysin; System; Techniques; Testing; Therapeutic; Therapeutic Effect; Time; Tissue Grafts; Tissues; Tracer; Transgenic Organisms; Transplantation; Treadmill Tests; Treatment Efficacy; Urination; Urodynamics; Weight; Work; awake; axon growth; axon regeneration; base; behavior test; biotinylated dextran amine; cryostat; density; design; dorsal column; graft function; improved; improved functioning; in vivo; injured; interest; laser capture microdissection; light microscopy; macrophage; migration; minimally invasive; motor deficit; myelination; nerve stem cell; neuroprotection; neurotrophic factor; regenerative; relating to nervous system; repaired; research study; response; tissue fixing; transcriptional coactivator p75; treatment strategy; versican; white matter

Our long term objectives are to develop effective transplantation strategies for treatment of spinal cord injury using well-defined neural stem cells. Despite the potential to replace cells and repair damaged CNS, the therapeutic value of this approach remains unproven. We have shown that lineage-restricted precursors (NPC) composed of neuronal and glial restricted precursors (NRP and GRP, respectively) can be isolated from transgenic AP rats and used for reliable fate analysis. When grafted into the adult CNS, they survive and differentiate into distinct neural phenotypes. Together the NRP/GRP create a micro-environment that allows robust neuronal differentiation in the injured spinal cord and support recovery of function. The neurons produced by the NPC graft integrate with host tissue, form synapses and project long axons that could potentially circumvent the poor regenerative capacity of the injured host. We propose to test specific hypotheses that grafts of lineage restricted precursors can repopulate the site of spinal cord injury, integrate with the host, promote sprouting, myelination and host protection, and reconstruct interrupted connections by forming functional relays with targets. Because the properties of the NPC are likely to be affected by the host microenvironment, we will test the role of specific therapeutic mechanisms in selected injury systems. In Aim 1 we will follow our studies that showed recovery in a contusion injury by examining how the NPC graft can modify the injury environment and whether recovery is mediated through sparing and sprouting. In Aim 2 we will test the ability of graft-derived neurons to establish active connections with the host and form a functional relay between the severed dorsal column axons and their target resulting in recovery of sensory deficits. Aim 3 will examine whether NPCs can promote axon growth in a lateral funiculus injury by connecting the axotomized rubrospinal tract and local circuits. The therapeutic efficacy and mechanisms of the NPC graft will be examined by a series of behavioral and physiological tests as well as analysis of the NPC expression profile and graft ablation. To maximize the therapeutic effects, the NPC grafts will be combined with treatments that improve axon growth and tested for delivery by a minimally invasive technique. Taken together, these experiments will test the specific elements of our hypothesis with respect to the role of lineage restricted precursors to participate and contribute to multiple stages of the recovery process.

我们的长期目标是制定有效的移植策略来治疗脊髓损伤 使用定义明确的神经干细胞。尽管有可能替代细胞并修复受损的中枢神经系统，但 这种方法的治疗价值尚未得到证实。我们已经证明了谱系限制的前体 （NPC）由神经元和神经胶质限制前体（分别为NRP和GRP）组成 来自转基因AP大鼠，用于可靠的命运分析。当嫁接到成人中枢神经系统中时，它们存活 并分化为不同的神经表型。 NRP/GRP共同创建一个微环境 允许受伤的脊髓中有强大的神经元分化并支持功能的恢复。神经元 由NPC移植物与宿主组织，形成突触和长轴突产生 潜在地避免受伤宿主的再生能力差。我们建议测试特定 假设谱系限制前体的移植物可以重新填充脊髓损伤部位，并整合 使用主机，促进发芽，髓鞘化和宿主保护，并通过 用目标形成功能继电器。因为NPC的特性可能会受到主机的影响 微环境，我们将测试特定治疗机制在选定损伤系统中的作用。目标 1我们将遵循我们的研究，该研究表明，通过检查NPC移植的方式可以通过 修改伤害环境以及是否通过避免和发芽来介导恢复。在目标2中我们 将测试移植物来源神经元与宿主建立主动连接的能力并形成功能 断层背柱轴突及其目标之间的继电器导致感觉缺陷的恢复。目的 3将检查NPC是否可以通过连接横向真实损伤中的轴突生长 轴刺脊髓和局部电路。 NPC移植物的治疗功效和机制 将通过一系列行为和生理测试以及NPC表达的分析来检查 轮廓和移植消融。为了最大化治疗效果，NPC移植物将与 改善轴突生长并通过微创技术进行递送的治疗方法。拍摄 这些实验将共同测试我们假设的特定元素 谱系限制前体参与并有助于恢复过程的多个阶段。