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中文摘要
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描述(申请人提供):少突胶质细胞(OLG)谱系的细胞成熟的特征是细胞形态的广泛变化。这些变化在很大程度上是由肌动蛋白细胞骨架的变化驱动的。有趣的是,在 中枢神经系统(CNS)患者患有人类主要的脱髓鞘疾病多发性硬化症,OLG分化似乎受阻,肌动蛋白细胞骨架调控机制失调。因此,作为一种更好地了解如何在病理条件下实现髓鞘修复的方法,本次拨款申请中提出的研究的长期目标是深入了解肌动蛋白细胞骨架调节机制在OLG分化和中枢神经系统髓鞘形成的总体控制中的作用。我们最近发表的初步研究证实,钙/钙调蛋白依赖的蛋白激酶II(CaMKII)是一个很好的候选因子,可以调节OLG肌动蛋白细胞骨架的动态稳定性和动态重塑,从而调节OLG的成熟和中枢神经系统的髓鞘形成。基于我们的数据,我们提出了我们的中心假设,即CaMKII?作为一种关键参与控制的肌动蛋白细胞骨架调节蛋白,在区分OLG方面起作用 OLG成熟和髓鞘形成的形态特征。为了解决这一假设,我们将完成以下两个具体目标:1)我们将在体内表征OLG来源的CaMKII在调节发育髓鞘形成和髓鞘相关肌动蛋白细胞骨架中的作用;2)我们将在体外表征CaMKII及其肌动蛋白结合/稳定结构域在调节分化的OLG和OLG的肌动蛋白细胞骨架中的作用。综上所述,作为这项赠款提案的一部分,将完成的实验有望为进一步评估TH CaMKII-肌动蛋白细胞骨架轴在中枢神经系统髓鞘形成和再髓鞘形成中的作用奠定基础,从而有助于更好地了解如何在病理性脱髓鞘条件下刺激中枢神经系统修复。
英文摘要
DESCRIPTION (provided by applicant): Maturation of cells of the oligodendrocyte (OLG) lineage is characterized by extensive changes in cellular morphology. These changes are to a large extent driven by changes in the actin cytoskeleton. Interestingly, within lesions seen in the central nervous system (CNS) of patients suffering from the major human demyelinating disease Multiple Sclerosis, OLG differentiation appears blocked and actin cytoskeleton regulatory mechanisms misregulated. Thus and as an approach toward a better understanding on how to achieve myelin repair under pathological conditions, the long-term goal of the studies proposed in this grant application is to gain insight into the role of actin cytoskeleton regulator mechanisms in the overall control of OLG differentiation and CNS myelination. Our recently published and preliminary studies identified calcium/calmodulin-dependent protein kinase Ii¿ (CaMKII¿) as a good candidate for a factor that can modulate kinetic stability versus dynamic remodeling of the OLG's actin cytoskeleton and thereby regulate OLG maturation and CNS myelination. Based on our data we propose as our central hypothesis that CaMKII¿ acts in differentiating OLGs as an actin cytoskeleton regulatory protein critically involved in controlling the morphological aspects of OLG maturation and myelination. To address this hypothesis we will complete the following two specific aims: 1) we will characterize in vivo the role of OLGderived CaMKII¿ in regulating developmental myelination and the myelin-associated actin cytoskeleton and 2) we will characterize in vitro the role of CaMKII¿ and its actin binding/ stabilizing domain in regulating the maturation of differentiating OLG and the OLG's actin cytoskeleton. Taken together, the experiments to be completed as part of this grant proposal are anticipated to build the basis for continuing studies in which to further assess the role of th CaMKII¿-actin cytoskeleton axis in CNS myelination as well as remyelination and to thus contribute to a better understanding on how to stimulate CNS repair under pathological demyelinating conditions.
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LPA6 signaling as a modulator of oligodendrocyte differentiation and CNS myelination
  • 批准号:
    10288115
  • 项目类别:
  • 资助金额:
    $41.59万
  • 财政年份:
    2021
  • 负责人:
    BABETTE FUSS
  • 依托单位:
47th Annual Meeting of the American Society for Neurochemistry
Glutamate transporters as regulators of CNS myelination
  • 批准号:
    8999028
  • 项目类别:
  • 资助金额:
    $22.88万
  • 财政年份:
    2015
  • 负责人:
    BABETTE FUSS
  • 依托单位:
PD-Ialpha/ATX's role for forebrain oligodendrocyte specification and migration
海外基金