Oligodendrocyte Genesis after Spinal Cord Injury

脊髓损伤后少突胶质细胞的发生

• 批准号: 7994743
• 负责人: DANA M MCTIGUE
• 金额: $ 32.95万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-01-05 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7994743
• 关键词: Adult; Astrocytes; Attention; Axon; CSPG4 gene; Cell Proliferation; Cells; Central Nervous System Diseases; Cessation of life; Chemicals; Chronic; Ciliary Neurotrophic Factor; Ciliary Neurotrophic Factor Receptor; Complement; Complex; Contusions; Data; Demyelinations; Environment; Evaluation; Exhibits; Fibroblast Growth Factor 2; Functional disorder; Goals; Health; Human; Immunofluorescence Immunologic; Inflammatory; Injury; Label; Lentivirus Vector; Lesion; Light; Link; Locomotor Recovery; Mediating; Methods; Microscopic; Mitotic; Modeling; Myelin; Nature; Necrosis; Oligodendroglia; Pathology; Plant Resins; Population; Production; Recovery; Recovery of Function; Regulation; Replacement Therapy; Resolution; Rodent; Role; Signal Pathway; Signaling Molecule; Site; Small Interfering RNA; Spinal; Spinal Cord; Spinal Remyelination; Spinal cord injury; Stem cells; Techniques; Technology; Testing; Therapeutic; Tissues; Transplantation; Up-Regulation; Viral; base; cell type; clinically relevant; design; follow-up; functional loss; gliogenesis; injured; insight; myelination; novel; progenitor; repaired; response; stem

DESCRIPTION (provided by applicant): Protracted oligodendrocyte (OL) death occurs after spinal cord injury (SCI). Because these cells myelinate axons, their loss leads to axon dysfunction and contributes to functional loss after SCI. Although many studies have characterized OL death after SCI, few have examined whether endogenous OL replacement occurs. We recently noted that a large number of new OLs are generated in the rim of tissue surrounding the lesion cavity after SCI. In the current proposal, these exciting findings will be followed up by determining if these new OLs contribute to axon remyelination and examining the mechanisms involved in their formation. Specifically, we will test the hypothesis that OL genesis in the traumatically injured adult spinal cord leads to remyelination of spinal axons and is dependent on astrocyte-derived CNTF. In Aim 1, we will expand upon preliminary data by characterizing the spatio-temporal extent of OL remyelination after SCI. Because only newly generated OLs can remyelinate axons, this data will provide information on the extent that the new cells contribute to endogenous repair. To complement this data, we will use GFP-retroviral lineage tracing to examine the fate of dividing cells after injury and to fluorescently label newly derived OLs and myelin ensheathing axons. These studies will be followed up in Aim 2 by examining the extent to which new OL genesis and OL remyelination depend on the presence of CNTF after SCI. Lentiviral-siRNA technology will be used to silence CNTF expression and spinal cords will be examined for changes in oligodendrocyte progenitor proliferation, new OL formation and myelination. Based on our pilot data, we predict that the number of OLs along lesion borders will be significantly reduced thereby leading to a decrease in remyelination of spinal axons. We will also examine the functional consequences of the absence of CNTF and reduction on oligogenesis. In Aim 3, we will examine the mechanisms of action for CNTF-mediated effects, including evaluating cellular expression of CNTF receptors and intracellular signaling molecules. Since CNTF is known to stimulate FGF-2 production and we and others show that FGF-2 is upregulated after SCI, we will also evaluate whether CNTF is essential for post-SCI FGF-2 expression. Collectively, the data generated will provide novel information on regulation of new OL formation in the injured adult CNS and the ability of these cells to help repair the damage induced by traumatic SCI. PUBLIC HEALTH RELEVANCE The relevance of this proposal is that the data will shed light on how new cells are formed after injury to the spinal cord and whether the new cells can help repair the damage. By understanding what controls the new cell formation, we will gain an understanding of what the cells are capable of doing and how to manipulate the injury site to enhance their reparative abilities.

描述(由申请人提供)：脊髓损伤(SCI)后发生延迟性少突胶质细胞(OL)死亡。因为这些细胞有髓鞘轴突，它们的丢失导致轴突功能障碍，并导致脊髓损伤后的功能丧失。尽管许多研究都描述了脊髓损伤后OL死亡的特征，但很少有人研究是否发生内源性OL替代。我们最近注意到，脊髓损伤后，在病变腔周围的组织边缘产生了大量新的OL。在目前的提案中，这些令人兴奋的发现之后将确定这些新的OL是否有助于轴突的重新髓鞘形成，并检查它们形成的机制。具体地说，我们将测试这一假设，即创伤损伤的成人脊髓中OL的发生导致脊髓轴突的重新髓鞘形成，并依赖于星形胶质细胞来源的CNTF。在目标1中，我们将通过描述脊髓损伤后OL髓鞘再生的时空范围来扩展初步数据。因为只有新生成的OL才能使轴突重新髓鞘形成，这一数据将提供有关新细胞对内源性修复做出贡献的程度的信息。为了补充这一数据，我们将使用GFP-逆转录病毒谱系追踪来检查损伤后细胞分裂的命运，并荧光标记新衍生的OL和髓鞘轴突。这些研究将在目标2中通过检查脊髓损伤后新的OL的发生和OL的再髓鞘形成依赖于CNTF的存在的程度来进行。慢病毒siRNA技术将被用来沉默CNTF的表达，脊髓将被检查少突胶质前体细胞增殖、新的OL形成和髓鞘形成的变化。根据我们的试验数据，我们预测沿着病变边缘的OL的数量将显著减少，从而导致脊髓轴突重新髓鞘形成的减少。我们还将研究CNTF的缺失和减少对寡聚细胞生成的功能影响。在目标3中，我们将研究CNTF介导的效应的作用机制，包括评估CNTF受体和细胞内信号分子的细胞表达。由于CNTF可以刺激成纤维细胞生长因子-2的产生，我们和其他人证明了脊髓损伤后成纤维细胞生长因子-2的表达上调，我们还将评估CNTF是否对脊髓损伤后成纤维细胞生长因子-2的表达是必需的。总之，所产生的数据将提供关于损伤的成年中枢神经系统中新的OL形成的调节以及这些细胞帮助修复创伤性脊髓损伤所致损伤的能力的新信息。公共卫生相关性这项提议的相关性在于，这些数据将阐明脊髓损伤后新细胞是如何形成的，以及新细胞是否可以帮助修复损伤。通过了解是什么控制了新细胞的形成，我们将了解细胞能够做什么，以及如何操纵损伤部位来增强它们的修复能力。