Glutamate transporters as regulators of CNS myelination

谷氨酸转运蛋白作为中枢神经系统髓鞘形成的调节剂

• 批准号: 8999028
• 负责人: BABETTE FUSS
• 金额: $ 22.88万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8999028
• 关键词: Actins; Address; Affect; Agreement; Applications Grants; Axon; Binding; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium/calmodulin-dependent protein kinase; Cells; Complex; Cytoskeleton; Data; Defect; Demyelinating Diseases; Demyelinations; Development; Disease; Gene Expression; Generations; Glutamate Transporter; Glutamates; Goals; Health; Human; In Vitro; Isoenzymes; Knock-out; Knockout Mice; Mediating; Microfilaments; Molecular; Morphogenesis; Morphology; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Myelin Sheath; Neuraxis; Neurologic; Oligodendroglia; Pathologic; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Process; Property; Publishing; Regulation; Research; Role; Signal Pathway; Signal Transduction; Sodium; Testing; Therapeutic; Therapeutic Intervention; Thick; base; calmodulin-dependent protein kinase II; curative treatments; extracellular; genetic regulatory protein; improved; in vivo; insight; knockout gene; multiple sclerosis treatment; mutant; myelination; new therapeutic target; novel; progenitor; remyelination; repaired; research study; therapeutic target

 DESCRIPTION (provided by applicant): Oligodendrocytes (OLGs), the myelinating cells of the central nervous system (CNS), undergo extensive changes in morphology when they mature first from bipolar OLG progenitors into premyelinating OLGs extending a complex and expanded process network and then into mature OLGs generating the myelin sheath. The morphological changes associated with this lineage progression are to a large extent driven by changes in the organization of the actin cytoskeleton, which require a well-coordinated dynamic turnover of actin filaments and are thought to be regulated by extracellular signals, which may, at least in part, be axon-derived. Despite intensive research, however, the signaling pathways involved in regulating such extracellular signal-regulated changes in actin cytoskeleton-driven OLG morphology, i.e. OLG morphogenesis, and CNS myelination are currently only poorly characterized. Notably, both changes in the extracellular milieu and a misregulation of actin cytoskeletal mechanisms have been proposed to contribute to the limitations in OLG morphogenesis and remyelination as seen within the CNS of the major demyelinating disease in human, Multiple Sclerosis (MS). Thus and in an attempt to identify novel therapeutic targets for the treatment of MS, our long-term goal is to identify and characterize signaling axes that promote developmental OLG morphogenesis and CNS myelination via an extracellular signal to actin cytoskeleton pathway but are misregulated within MS lesions. In this regard, our preliminary data suggest that a signaling axis involving the activity of sodium- dependent glutamate transporters and subsequent changes in the actin-binding activity of calcium/calmodulin- dependent protein kinase IIß (CaMKIIß) is critical for efficient OLG morphogenesis and the generation of a myelin sheath of proper thickness (g-ratio). Notably, our preliminary data together with previously published findings point toward a misregulation of this signaling axis within MS lesions. Based on our preliminary data, we thus formulate the central hypothesis that efficient myelination, i.e. the establishment of myelin with a proper g-ratio, is regulated by a glutamate transporter-CaMKIIß-actin cytoskeleton axis that is operative within differentiating OLGs. To address the above stated central hypothesis we propose the completion of the following two specific aims: 1) to characterize in vivo the role of the apparentl functionally predominant sodium-dependent glutamate transporter in differentiating OLGs, GLT-1, in regulating developmental myelination and 2) to characterize in vitro the role of the glutamate transporter-CaMKIIß-actin cytoskeleton axis in regulating OLG morphogenesis. We anticipate that these experiments will build the basis for continuing studies in which to define strategies to specifically target CaMKIIß's unique actin binding properties and/or GLT-1 signaling as an attempt toward the development of novel remyelination promoting therapeutic strategies and toward improving the treatment of neurologic diseases associated with CNS demyelination.

 描述（由申请人提供）：少突胶质细胞（OLG）是中枢神经系统（CNS）的髓鞘形成细胞，当它们首先从双极OLG祖细胞成熟为延伸出复杂且扩展的过程网络的髓鞘形成前OLG，然后发育为产生髓鞘的成熟OLG时，它们会经历广泛的形态变化。与这种谱系进展相关的形态变化在很大程度上是由肌动蛋白细胞骨架组织的变化驱动的，这需要肌动蛋白丝的良好协调的动态周转，并且被认为受到细胞外信号的调节，这些信号可能至少部分来自轴突。然而，尽管进行了深入的研究，但目前对参与调节肌动蛋白细胞骨架驱动的 OLG 形态的细胞外信号调节变化（即 OLG 形态发生和 CNS 髓鞘形成）的信号通路的特征还很不清楚。值得注意的是，细胞外环境的变化和肌动蛋白细胞骨架机制的失调都被认为导致 OLG 形态发生和髓鞘再生的限制，如人类主要脱髓鞘疾病多发性硬化症 (MS) 的 CNS 中所见。因此，在尝试确定治疗多发性硬化症的新治疗靶点时，我们的长期目标是确定和表征信号轴，这些信号轴通过肌动蛋白细胞骨架途径的细胞外信号促进发育性 OLG 形态发生和中枢神经系统髓鞘形成，但在多发性硬化症病变内受到错误调节。在这方面，我们的初步数据表明，涉及钠依赖性谷氨酸转运蛋白活性的信号轴以及钙/钙调蛋白依赖性蛋白激酶IIß（CaMKIIß）肌动蛋白结合活性的后续变化对于有效的OLG形态发生和适当厚度（g比）的髓鞘的生成至关重要。值得注意的是，我们的初步数据以及之前发表的研究结果表明，多发性硬化症病变内的信号轴存在失调。基于我们的初步数据，我们提出了中心假设，即有效的髓鞘形成，即具有适当 g 比率的髓磷脂的建立，是由在分化 OLG 中起作用的谷氨酸转运蛋白 -CaMKIIß -肌动蛋白细胞骨架轴调节的。为了解决上述中心假设，我们建议完成以下两个具体目标：1）在体内表征明显功能上占主导地位的钠依赖性谷氨酸转运蛋白在分化 OLG、GLT-1 中的作用，在调节发育髓鞘形成中的作用；2）在体外表征谷氨酸转运蛋白 -CaMKIIß-肌动蛋白细胞骨架轴在发育髓鞘形成中的作用。 调节 OLG 形态发生。我们预计这些实验将为继续研究奠定基础，以确定专门针对 CaMKIIß 独特的肌动蛋白结合特性和/或 GLT-1 信号传导的策略，以尝试开发新的髓鞘再生促进治疗策略并改善与 CNS 脱髓鞘相关的神经系统疾病的治疗。