CaMKIIbeta: a regulator of CNS myelination

CaMKIIbeta：中枢神经系统髓鞘形成的调节因子

• 批准号: 8707006
• 负责人: BABETTE FUSS
• 金额: $ 19.06万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8707006
• 关键词: Actins; Address; Affect; Agreement; Applications Grants; Axon; Binding; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium/calmodulin-dependent protein kinase; Cell Lineage; Cell Maturation; Cells; Cellular Morphology; Complex; Cytoskeleton; Data; Demyelinating Diseases; Demyelinations; Dendritic Spines; Development; Equilibrium; Family member; Gene Expression; Goals; Growth Cones; Human; In Vitro; Kinetics; Knock-out; Knockout Mice; Lesion; Microfilaments; Molecular; Morphology; Multiple Sclerosis; Multiple Sclerosis Lesions; Mutation; Myelin; Myelin Sheath; Neuraxis; Neurons; Oligodendroglia; Patients; Phosphotransferases; Prevalence; Process; Property; Protein Family; Protein-Serine-Threonine Kinases; Publishing; Regulation; Role; Signal Transduction; Testing; Time; base; calmodulin-dependent protein kinase II; genetic regulatory protein; in vivo; insight; member; myelination; nervous system disorder; oligodendrocyte lineage; prevent; progenitor; public health relevance; remyelination; repaired; research study

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.

描述（由申请人提供）：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，在所见的病变内 患有人类主要脱髓鞘疾病多发性硬化症的中枢神经系统（CNS）患者，OLG分化出现受阻，肌动蛋白细胞骨架调节机制失调。因此，作为更好地了解如何在病理条件下实现髓磷脂修复的一种方法，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总体控制中的作用。我们最近发表的初步研究发现，钙/钙调蛋白依赖性蛋白激酶 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力学稳定性与动态重塑，从而调节 OLG 成熟和中枢神经系统髓鞘形成。根据我们的数据，我们提出中心假设，即 CaMKII 作为肌动蛋白细胞骨架调节蛋白，在 OLG 的分化中发挥作用，关键参与控制 OLG 成熟和髓鞘形成的形态学方面。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 衍生的 CaMKII 在调节发育髓鞘形成和髓磷脂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 OLG 和 OLG 肌动蛋白成熟中的作用 细胞骨架。总而言之，作为本拨款提案的一部分即将完成的实验预计将为继续研究奠定基础，进一步评估 CaMKII-肌动蛋白细胞骨架轴在中枢神经系统髓鞘形成和髓鞘再生中的作用，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。