CaMKIIbeta: a regulator of CNS myelination
CaMKIIbeta: a regulator of CNS myelination
批准号:
8707006
负责人:
BABETTE FUSS
金额:
$19.06万
依托单位国家:
美国
项目类别:
财政年份:
2014
资助国家:
美国
项目状态:
已结题
起止时间:
2014-04-01 至 2016-03-31
关键词:
ActinsAddressAffectAgreementApplications GrantsAxonBindingCa(2+)-Calmodulin Dependent Protein KinaseCalcium/calmodulin-dependent protein kinaseCell LineageCell MaturationCellsCellular MorphologyComplexCytoskeletonDataDemyelinating DiseasesDemyelinationsDendritic SpinesDevelopmentEquilibriumFamily memberGene ExpressionGoalsGrowth ConesHumanIn VitroKineticsKnock-outKnockout MiceLesionMicrofilamentsMolecularMorphologyMultiple SclerosisMultiple Sclerosis LesionsMutationMyelinMyelin SheathNeuraxisNeuronsOligodendrogliaPatientsPhosphotransferasesPrevalenceProcessPropertyProtein FamilyProtein-Serine-Threonine KinasesPublishingRegulationRoleSignal TransductionTestingTimebasecalmodulin-dependent protein kinase IIgenetic regulatory proteinin vivoinsightmembermyelinationnervous system disorderoligodendrocyte lineagepreventprogenitorpublic health relevanceremyelinationrepairedresearch study
中文摘要
描述(由申请方提供):少突胶质细胞(OLG)谱系细胞的成熟以细胞形态的广泛变化为特征。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,在病变中,
患有人类主要脱髓鞘疾病多发性硬化症的患者的中枢神经系统(CNS),OLG分化似乎被阻断并且肌动蛋白细胞骨架调节机制失调。因此,作为一种更好地理解如何在病理条件下实现髓鞘修复的方法,本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CNS髓鞘形成的整体控制中的作用。我们最近发表的和初步的研究确定钙/钙调蛋白依赖性蛋白激酶Ii <$$>(CaMKII <$)作为一个很好的候选因子,可以调节动力学稳定性与动态重塑的OLG的肌动蛋白细胞骨架,从而调节OLG成熟和中枢神经系统髓鞘形成。基于我们的数据,我们提出了我们的中心假设,即CaMKII作为一种肌动蛋白细胞骨架调节蛋白,在分化OLG中起作用,
OLG成熟和髓鞘形成的形态学方面。为了解决这一假设,我们将完成以下两个具体目标:1)我们将在体内表征OLG衍生的CaMKII?在调节发育髓鞘形成和髓鞘相关肌动蛋白细胞骨架中的作用,2)我们将在体外表征CaMKII?及其肌动蛋白结合/稳定结构域在调节分化OLG和OLG肌动蛋白细胞骨架成熟中的作用。综上所述,作为本拨款提案的一部分,预计将完成的实验将为继续研究奠定基础,进一步评估CaMKII <$-肌动蛋白细胞骨架轴在CNS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CNS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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