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）后发生持久的少突胶质细胞（OL）死亡。由于这些细胞髓鞘轴突，它们的损耗会导致轴突功能障碍，并在SCI后导致功能损失。尽管许多研究表征了SC​​I之后的OL死亡，但很少有人检查了内源性替代是否发生。我们最近注意到，在SCI后，在病变腔周围的组织边缘产生了大量新OL。在当前的提案中，这些令人兴奋的发现将随后确定这些新的OLS是否有助于轴突再髓样并检查其形成所涉及的机制。具体而言，我们将检验以下假设：创伤损伤的成年脊髓中的OL发生会导致脊柱轴突再髓鞘，并且依赖于星形胶质细胞衍生的CNTF。在AIM 1中，我们将通过表征SCI后OL再生的时空范围来扩展初步数据。由于只有新生成的OLS才能重新安排轴突，因此该数据将提供有关新细胞有助于内源性修复程度的信息。为了补充这些数据，我们将使用GFP-逆转录病毒谱系跟踪来检查损伤后分裂细胞的命运，并荧光标记新得出的OLS和髓磷脂轴突。通过研究新的OL Genesis和Ol Remerelation取决于SCI后CNTF的存在，将在AIM 2中跟进这些研究。慢病毒 - siRNA技术将用于沉默CNTF表达，并将检查脊髓的少突胶质细胞祖细胞增殖，新的OL形成和髓鞘形式的变化。根据我们的试点数据，我们预测，沿着病变边界的OL数量将大大减少，从而导致脊柱轴突的再髓质减少。我们还将检查缺乏CNTF和减少寡聚发生的功能后果。在AIM 3中，我们将检查CNTF介导作用的作用机理，包括评估CNTF受体的细胞表达和细胞内信号分子。由于已知CNTF刺激FGF-2的产生，我们和其他人表明SCI后FGF-2上调，我们还将评估CNTF是否对于SCI后SCI FGF-2表达至关重要。总体而言，生成的数据将提供有关受伤成年中枢神经系统中新OL形成的调节的新信息，以及这些细胞有助于修复创伤性SCI造成的损害的能力。 公共卫生相关性的相关性是，数据将阐明脊髓受伤后的新细胞以及新细胞是否可以帮助修复损坏。通过了解控制新细胞形成的因素，我们将了解细胞的能力以及如何操纵伤害部位以增强其修复能力。