Role of ERK1/ERK2 MAP Kinase in Myelin Assembly and Maintenance
ERK1/ERK2 MAP 激酶在髓磷脂组装和维护中的作用
基本信息
- 批准号:8531406
- 负责人:
- 金额:$ 23.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-02-15 至 2015-01-31
- 项目状态:已结题
- 来源:
- 关键词:AblationAddressAdultAutomobile DrivingAxonCaliberCellsComplexDataDemyelinating DiseasesDevelopmentEnvironmentEventFoundationsFutureGene ExpressionGenesGeneticGenetic TranscriptionGoalsGrowthHumanIn VitroInterventionInvestigationKnockout MiceKnowledgeLong-Term EffectsMAP Kinase GeneMAPK1 geneMAPK10 geneMAPK3 geneMaintenanceMediatingMediator of activation proteinMitogen-Activated Protein KinasesMultiple SclerosisMultiple Sclerosis LesionsMusMyelinMyelin SheathOligodendrogliaPathway interactionsPhasePhosphotransferasesPlayProcessProliferatingRegulationRoleSeriesSignal PathwaySignal TransductionSignaling MoleculeStagingTamoxifenThickTimeTransgenic Micebaseclinically relevantdesignfunctional disabilitygain of functionhuman FRAP1 proteinin vivoinsightmouse modelmyelin biogenesismyelinationoligodendrocyte lineagepostnatalprogenitorpublic health relevanceremyelination
项目摘要
DESCRIPTION (provided by applicant): Wrapping of the myelin sheath around axons by oligodendrocytes (OLs) is critical for the rapid conduction of electrical signals that are required
for normal functioning of the CNS. Myelination is a multistep process involving the proliferation of OL progenitors (OPCs), timely differentiation into OLs, ensheathment of axons and finally rapid expansion of myelin sheath during the peak of myelination followed by gradual growth in adulthood. While many regulators of the early stages of OL development have been identified, there are significant gaps in our understanding of the specific intracellular signaling events that
are integrated within the OLs that control later phases of myelinogenesis to increase its thickness in proportion to axon caliber. Understanding this mechanism is clinically relevant since it is unclear why the myelin that is formed during remyelination in Multiple Sclerosis fails to achieve normal thickness. This proposal primarily addresses the important question of how myelin assembly and maintenance are regulated in the CNS, hypothesizing that ERK1/2-MAPK (Extracelluar Signal Regulated Kinases-1/2), important mediators of multiple external signals, plays a central role in these processes. This is based on our recent findings that mice lacking OL-specific expression of ERK1/2 fail to up- regulate the transcription of major myelin genes and are unable to generate thick myelin sheaths. This is independent of OPC proliferation, differentiation and ensheathment of axons since these events remain unaffected in the Erk1/2 knockout mice. These results represent an important conceptual paradigm shift as they suggest that OL differentiation/initiation and subsequent increase in myelin thickness are distinctly regulated, in contrast to the PNS, where one signal controls both OL differentiation and myelination. To obtain further insights into the role of ERK1/2 in the complex in vivo environment, we seek to address the following specific questions using a series of transgenic mice models with genetic loss or gain of ERK1/2 function. In Aim I, using mice where ablation of Erk1/2 in mature OLs will be induced at a later point in development and in adulthood, we will examine the role of ERK1/2 on the long- term progression of myelin growth and maintenance in adulthood. In Aim II, using mice where ERK1/2 activity will be elevated in OPCs and OLs during development or in mature OLs during adulthood, we will elucidate the role of ERK1/2 in OL development and myelin assembly during active myelination and in adulthood. Overall, a combination of state-of-the-art genetic loss- and gain-of-function approaches as proposed here are expected to enhance our understanding of the functional significance of ERK1/2 signaling both during OL differentiation and active myelin biogenesis, as well as to sustain its gradual growth and maintenance in adulthood, and to apply this knowledge for an informed intervention in the treatment of demyelinating diseases such as MS.
描述(由申请人提供):少突胶质细胞(OL)将髓鞘包裹在轴突周围对于快速传导所需的电信号至关重要
以保证中枢神经系统的正常运作。髓鞘形成是一个多步骤的过程,涉及 OL 祖细胞 (OPC) 的增殖、及时分化为 OL、轴突形成鞘,最后在髓鞘形成高峰期间髓鞘快速扩张,随后在成年期逐渐生长。虽然 OL 发育早期阶段的许多调节因子已被确定,但我们对导致 OL 发育早期阶段的特定细胞内信号转导事件的理解仍存在显着差距。
整合在控制髓鞘形成后期的 OL 中,以与轴突直径成比例地增加其厚度。了解这一机制具有临床意义,因为尚不清楚多发性硬化症髓鞘再生过程中形成的髓磷脂为何无法达到正常厚度。该提案主要解决了中枢神经系统中髓磷脂组装和维护如何调节的重要问题,假设 ERK1/2-MAPK(细胞外信号调节激酶-1/2)作为多种外部信号的重要介质,在这些过程中发挥核心作用。这是基于我们最近的发现,即缺乏 ERK1/2 OL 特异性表达的小鼠无法上调主要髓磷脂基因的转录,并且无法生成厚髓鞘。这与 OPC 增殖、分化和轴突鞘化无关,因为这些事件在 Erk1/2 敲除小鼠中不受影响。这些结果代表了一个重要的概念范式转变,因为它们表明 OL 分化/起始和随后髓鞘厚度的增加受到明显调节,而 PNS 则相反,其中一个信号控制 OL 分化和髓鞘形成。为了进一步了解 ERK1/2 在复杂的体内环境中的作用,我们试图使用一系列具有 ERK1/2 功能遗传缺失或获得的转基因小鼠模型来解决以下具体问题。在目标 I 中,我们将使用在发育后期和成年期诱导成熟 OL 中 Erk1/2 消融的小鼠,研究 ERK1/2 对成年期髓磷脂生长和维持的长期进展的作用。在 Aim II 中,使用在发育过程中 OPC 和 OL 中或成年期成熟 OL 中 ERK1/2 活性升高的小鼠,我们将阐明 ERK1/2 在活跃髓鞘形成期间和成年期的 OL 发育和髓磷脂组装中的作用。总体而言,本文提出的最先进的遗传功能丧失和功能获得方法的结合有望增强我们对 OL 分化和活跃髓磷脂生物发生过程中 ERK1/2 信号传导的功能意义的理解,以及维持其在成年期的逐渐生长和维持,并将这些知识应用于治疗多发性硬化症等脱髓鞘疾病的知情干预。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
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RASHMI BANSAL其他文献
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{{ truncateString('RASHMI BANSAL', 18)}}的其他基金
Role of ERK1/ERK2 MAP Kinase in Myelin Assembly and Maintenance
ERK1/ERK2 MAP 激酶在髓磷脂组装和维护中的作用
- 批准号:
8611978 - 财政年份:2013
- 资助金额:
$ 23.1万 - 项目类别:
PROTEOMIC MAPPING OF MYELIN AND ITS MEMBRANE SUBDOMAINS
髓磷脂及其膜亚域的蛋白质组图谱
- 批准号:
7260313 - 财政年份:2000
- 资助金额:
$ 23.1万 - 项目类别:
PROTEOMIC MAPPING OF MYELIN AND ITS MEMBRANE SUBDOMAINS
髓磷脂及其膜亚域的蛋白质组图谱
- 批准号:
7585702 - 财政年份:2000
- 资助金额:
$ 23.1万 - 项目类别:
PROTEOMIC MAPPING OF MYELIN AND ITS MEMBRANE SUBDOMAINS
髓磷脂及其膜亚域的蛋白质组图谱
- 批准号:
7442127 - 财政年份:2000
- 资助金额:
$ 23.1万 - 项目类别:
FGF RECEPTOR FUNCTION IN OLIGODENDROCYTE DIFFERENTIATION
FGF 受体在少突胶质细胞分化中的功能
- 批准号:
6540107 - 财政年份:1999
- 资助金额:
$ 23.1万 - 项目类别:
FGF Receptors in Myelin Function and Disease
FGF 受体在髓磷脂功能和疾病中的作用
- 批准号:
6906406 - 财政年份:1999
- 资助金额:
$ 23.1万 - 项目类别:
FGF Receptor in Myelin Function and Disease
FGF 受体在髓磷脂功能和疾病中的作用
- 批准号:
8089229 - 财政年份:1999
- 资助金额:
$ 23.1万 - 项目类别:
FGF Receptor in Myelin Function and Disease
FGF 受体在髓磷脂功能和疾病中的作用
- 批准号:
7911968 - 财政年份:1999
- 资助金额:
$ 23.1万 - 项目类别:
FGF Receptors in Myelin Function and Disease
FGF 受体在髓磷脂功能和疾病中的作用
- 批准号:
7252348 - 财政年份:1999
- 资助金额:
$ 23.1万 - 项目类别:
FGF Receptors in Myelin Function and Disease
FGF 受体在髓磷脂功能和疾病中的作用
- 批准号:
7082778 - 财政年份:1999
- 资助金额:
$ 23.1万 - 项目类别:
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