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首页> 外文学位 >The role of sodium channel alpha and beta subunits in myelinating glia and demyelinating disorders.
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The role of sodium channel alpha and beta subunits in myelinating glia and demyelinating disorders.

机译：钠通道α和β亚基在髓鞘神经胶质和脱髓鞘疾病中的作用。

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摘要

Multiple sclerosis (MS) is a demyelinating inflammatory disease of the central nervous system (CNS) in which patients experience a variety of neurological symptoms resulting from demyelination, axonal degeneration and axonal loss leading to conduction block or aberrant conduction. Voltage-gated sodium channels (VGSCs) have been implicated in the pathogenesis of MS and its animal model, Experimental Allergic Encephalomyelitis (EAE). We previously generated a Scn2b (VGSC beta2) null mouse which exhibits a 40-50% decrease in neuronal VGSC cell surface expression. We hypothesized that Scn2b deletion would result in neuroprotection in EAE due to a decrease in excitotoxicity. The goal of this thesis was to determine the role of VGSCs in CNS demyelinating disease and myelinating glia using three different systems: Scn2b null mice, human MS brain, and cultured rat oligodendrocytes.;Scn2b deletion led to improved clinical outcome in the EAE model, with mice displaying less severe clinical symptoms, decreases in lethality, and reductions in axonal loss, degeneration and demyelination. In EAE, these mice also displayed alterations in subcellular localization and protein expression levels of the VGSC a subunit Nav1.1, a channel which has not been studied previously in demyelinating disease. We then translated these experiments to the study of post-mortem human brain. MS brain displayed increased Nav1.1 protein levels in white and grey matter and changes in expression of beta subunits in glia as compared to control brain. Finally, we examined the expression of VGSC alpha and beta subunits in cultured rat oligodendrocytes at two stages of differentiation. These cells displayed differential expression of alpha and beta subunits, with VGSC alpha, beta1 and beta3 subunits expressed at both stages while beta2 and beta4 were expressed at low levels.;To summarize, the results presented in this thesis implicate VGSC beta2 and Nav1.1 subunits in the pathogenesis of CNS demyelinating disease in both human and mouse, and suggest roles for VGSC alpha and beta subunits in myelinating glial cell precursors. VGSC beta2 and Nav1.1 subunits may also offer novel targets for the development of therapeutics for the treatment of MS.
机译：多发性硬化症（MS）是中枢神经系统（CNS）的脱髓鞘炎性疾病，其中患者会经历由于脱髓鞘，轴突变性和轴突缺失导致的多种神经系统症状，导致传导阻滞或异常传导。电压门控钠通道（VGSCs）已参与MS及其动物模型实验性变应性脑脊髓炎（EAE）的发病机理。我们以前生成了Scn2b（VGSC beta2）空小鼠，它在神经元VGSC细胞表面表达中降低了40-50％。我们假设Scn2b缺失会由于兴奋性毒性降低而导致EAE中的神经保护。本论文的目的是使用以下三种不同的系统来确定VGSC在CNS脱髓鞘疾病和髓鞘神经胶质中的作用：Scn2b无效小鼠，人MS脑和培养的大鼠少突胶质细胞。Scn2b缺失可改善EAE模型的临床疗效，小鼠表现出较轻的临床症状，致死率降低，轴突损失，变性和脱髓鞘减少。在EAE中，这些小鼠还显示了VGSC亚单位Nav1.1的亚细胞定位和蛋白质表达水平的改变，该通道先前尚未在脱髓鞘疾病中研究过。然后，我们将这些实验翻译为人体后验尸的研究。与对照脑相比，MS脑在白质和灰质中显示出增加的Nav1.1蛋白水平，并在胶质细胞中表达了β亚基。最后，我们检查了在分化的两个阶段中培养的大鼠少突胶质细胞中VGSCα和β亚基的表达。这些细胞显示出α和β亚基的差异表达，VGSC的α，β1和β3亚基在两个阶段均表达，而β2和β4则以低水平表达。总之，本文提出的结果暗示了VGSC beta2和Nav1.1的存在。亚基在人和小鼠中枢神经系统脱髓鞘疾病的发病机理中的作用，并暗示了VGSCα和β亚基在有髓神经胶质细胞前体中的作用。 VGSC beta2和Nav1.1亚基也可能为开发用于MS治疗的疗法提供新的靶标。

著录项

  • 作者

    O'Malley, Heather A.;

  • 作者单位

    University of Michigan.;

  • 授予单位 University of Michigan.;
  • 学科 Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 282 p.
  • 总页数 282
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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