Deciphering the Daam2-VHL signaling axis in oligodendrocyte development and white matter injury
破译少突胶质细胞发育和白质损伤中的 Daam2-VHL 信号轴
基本信息
- 批准号:10556388
- 负责人:
- 金额:$ 34.67万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-02-01 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:BiochemicalCell LineageCellsCentral Nervous SystemComplexCouplingDataDefectDegradation PathwayDemyelinationsDevelopmentDevelopmental GeneDiseaseEctopic ExpressionEventExhibitsGene Expression ProfilingGenerationsGenesGeneticGenetic EpistasisGoalsHumanHypoxiaHypoxia PathwayHypoxic Brain DamageInjuryLigaseMediatingModelingMorphogenesisMusMyelinNerve DegenerationNervous System PhysiologyNeurogliaNeuronal DysfunctionNeuronsOligodendrogliaPathway interactionsPatternPlayPredispositionProteinsRegenerative capacityRoleSignal TransductionSystemTRIM MotifTestingUbiquitinUbiquitinationWNT Signaling Pathwayclinically actionableclinically significantemerging adultgain of functionglial cell developmenthypoxia neonatorumloss of functionmouse modelmyelinationnerve stem cellnervous system disorderneural circuitnoveloligodendrocyte myelinationoligodendrocyte progenitorprogramsprotein degradationreceptorremyelinationrepairedscreeningtherapeutic developmenttreatment strategyubiquitin-protein ligasewhite matterwhite matter damagewhite matter injury
项目摘要
SUMMARY and ABSTRACT
Glia comprise approximately 60% of the cellular constituency of central nervous system (CNS), playing diverse
roles in the functioning CNS and a host of neurological disorders. Development of glial cell lineages proceeds
along a tightly regulated program that involves patterning, generation of diverse cells, differentiation, and
myelination. This cascade of developmental events is particularly vulnerable to neonatal hypoxic brain injury,
which leads to profound loss of myelinating oligodendrocytes (OLs), extensive white matter damage,
culminating in neuronal dysfunction. Despite the robust regenerative capacity of OLs, the underlying
mechanisms mediating hypomyelination and the subsequent defects in neural circuits after hypoxic injury
remain poorly defined. Moreover, myelination continues throughout early adulthood, which also renders the
CNS susceptible to insults causing late-onset neurodegeneration. Therefore, the overarching goal of this
application is to define new genes and pathways that drive OL maturation during development and repair, and
pinpoint potential targetable pathways for white matter disorders. Previously, we identified Daam2
(Disheveled associated activator of morphogenesis 2) as a pivotal regulator of OL myelination and repair, and
recently discovered that Daam2 governs OL differentiation through ubiquitination of the hypoxia regulator
VHL (von Hippel-Lindau). Moreover, we discovered that Daam2 is regulated by two E3 ligases, Nedd4 (Neural
precursor cell expressed developmentally down-regulated protein 4) and Trim9 (Tripartite Motif Containing
9), which in turn govern VHL ubiquitination and OL differentiation. These observations raise two key
questions that we will pursue in this proposal: 1) how does Daam2 modulate VHL-HIF signaling in OLs? and 2)
how is the ubiquitin-mediated Daam2 degradation controlled in OLs? By understanding the in-depth
mechanisms by which Daam2 operates, we will establish Daam2 inhibition as a clinically significant and
actionable strategy for the treatment of white matter injury. To answer these key questions, we will first define
the reciprocal relationship between Daam2 and VHL during OL development and white matter injury (Aim 1).
These studies will define the Daam2-VHL axis as a pivotal regulator of OL development, while revealing novel
connections between Wnt signaling and hypoxic pathway during OL myelination. Next, we will determine
Daam2 proteasomal degradation pathways in OLs (Aim 2). Upon completion, these studies will define how
Daam2 is regulated by target E3 ligases, and identify Nedd4 and Trim9 as novel regulators of OL myelination.
A mechanistic understanding of Daam2-VHL axis function in oligodendrocyte repair after injury will shed light
on cellular vulnerability to white matter injury and ultimately point to new venues for therapeutic development
to stimulate OL remyelination.
内容和摘要
神经胶质细胞约占中枢神经系统(CNS)细胞组成的60%,具有多种功能。
在中枢神经系统功能和一系列神经系统疾病中的作用。神经胶质细胞谱系的发育
沿着一个严格调控的程序,涉及图案化,产生不同的细胞,分化,
髓鞘形成这种一连串的发育事件特别容易受到新生儿缺氧性脑损伤的影响,
其导致髓鞘形成少突胶质细胞(OL)的严重损失,广泛的白色物质损伤,
最终导致神经元功能障碍。尽管OL具有强大的再生能力,但潜在的
缺氧损伤后髓鞘形成减少及神经回路缺陷的机制
定义不明确。此外,髓鞘形成在整个成年早期持续,这也使得
CNS易受损伤,导致迟发性神经变性。因此,这一总体目标
应用是定义在发育和修复过程中驱动OL成熟的新基因和途径,
精确定位白色物质紊乱的潜在靶向途径。此前,我们确定了Daam 2
(形态发生的紊乱相关激活剂2)作为OL髓鞘形成和修复的关键调节剂,以及
最近发现Daam 2通过缺氧调节因子的泛素化来控制OL分化
VHL(von Hippel-Lindau).此外,我们发现Daam 2受两种E3连接酶Nedd 4(Neural
前体细胞表达的发育下调蛋白4)和Trim 9(含有三分基序的
9),这反过来又控制VHL泛素化和OL分化。这些观察提出了两个关键问题
我们将在这个提议中继续探讨的问题:1)Daam 2如何调节OL中的VHL-HIF信号传导?和2)
OLs中泛素介导的Daam 2降解是如何控制的?通过深入了解
Daam 2的运作机制,我们将建立Daam 2抑制作为一个临床意义,
治疗白色物质损伤的可行策略。为了回答这些关键问题,我们将首先定义
Daam 2和VHL在OL发育和白色损伤过程中的相互关系(目的1)。
这些研究将Daam 2-VHL轴定义为OL发育的关键调节因子,同时揭示了新的
OL髓鞘形成过程中Wnt信号与缺氧通路的关系。接下来,我们将确定
OL中的Daam 2蛋白酶体降解途径(Aim 2)。完成后,这些研究将确定如何
Daam 2受靶E3连接酶调控,并鉴定Nedd 4和Trim 9为OL髓鞘形成的新调控因子。
对损伤后少突胶质细胞修复中Daam 2-VHL轴功能的机制了解将为我们提供线索
细胞对白色物质损伤的脆弱性,并最终指出新的治疗方法的发展
刺激OL髓鞘再生。
项目成果
期刊论文数量(0)
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Hyun Kyoung Lee其他文献
Hyun Kyoung Lee的其他文献
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Deciphering Mechanisms of Astrocyte-BBB Interaction in Normal and Ischemic Stroke
解读正常和缺血性中风中星形胶质细胞-BBB相互作用的机制
- 批准号:
10585849 - 财政年份:2023
- 资助金额:
$ 34.67万 - 项目类别:
Deciphering the Daam2-VHL signaling axis in oligodendrocyte development and white matter injury
破译少突胶质细胞发育和白质损伤中的 Daam2-VHL 信号轴
- 批准号:
10338107 - 财政年份:2019
- 资助金额:
$ 34.67万 - 项目类别:
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