Astrocyte regulation of CNS remyelination
星形胶质细胞对中枢神经系统髓鞘再生的调节
基本信息
- 批准号:7869502
- 负责人:
- 金额:$ 23.73万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2008
- 资助国家:美国
- 起止时间:2008-03-15 至 2011-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAnimal ModelApoptosisAstrocytesAxonBiological PreservationClinicalCoculture TechniquesComplementDataDemyelinating DiseasesDemyelinationsDiseaseEnvironmentEventExperimental Autoimmune EncephalomyelitisFailureGoalsHumanImmunohistochemistryIn VitroIncidenceInflammationInflammatoryInterleukin-11LaboratoriesLesionLinkMediator of activation proteinMicroarray AnalysisMolecularMultiple SclerosisMultiple Sclerosis LesionsMusMyelinNatural regenerationNeuronsOligodendrogliaParaffinPlayRattusRecoveryRegulationRelapseResearchRodentRoleSeveritiesSignal PathwaySpinal GangliaStem cellsSymptomsTestingTissue SampleWorkastrogliosisbasecDNA Arrayscentral nervous system injurycytokineeponfunctional genomicshuman tissueimmunoreactivityimprovedinterleukin-11 receptorneuroprotectionnovel therapeuticsreceptorrepairedresearch studysuccess
项目摘要
DESCRIPTION (provided by applicant): Mechanisms that regulate oligodendrocyte survival and myelin formation are an intense focus of research into repair in the lesions of multiple sclerosis (MS). Demyelination and oligodendrocyte loss are pathological hallmarks of the disease, and although increased oligodendrocyte numbers and remyelination are frequently observed in early lesions, it is clear that remyelination gradually fails as MS progresses. Current treatments for MS aim to reduce the incidence and severity of new lesion formation and clinical relapses, but these approaches have, to date, demonstrated little beneficial effect on regeneration and remyelination. For this reason, myelin repair and neuroprotection remain major goals for MS research. Accumulating evidence suggests that mediators produced locally play an important role in determining the success or failure of repair MS plaques, and the keys to understanding remyelination may therefore lie in molecular study of the lesion environment. Reactive astrocytes represent the most abundant cellular component of the MS plaque, and have been implicated as regulators of CNS inflammation and regeneration. We have investigated potential links between astrocyte reactivity and lesion repair using microarray analysis of cytokine-treated human astrocytes, and this approach has identified interleukin-11 (IL-11) as an astrocyte- derived factor that regulates oligodendrocyte survival and maturation, and myelin formation. IL-11 is induced in human astrocyte cultures by treatment with cytokines known to be expressed in MS plaques. In MS tissue samples, IL-11 is expressed by reactive astrocytes, with expression particularly localized to the myelin- containing border of both active and silent lesions. Its receptor, IL-11R alpha, is expressed by oligodendrocytes. In human cultures in vitro, treatment with IL-11 results in a significant increase in oligodendrocyte number, and this is associated with enhanced oligodendrocyte survival and maturation. Importantly, we have also found that IL-11 treatment is associated with a significant increase in myelin formation in rodent CNS cocultures. In addition, preliminary data from our laboratory indicate that IL-11 is protective in an animal model of MS. In this application, we will test the hypothesis that cytokine-induced expression of IL-11 in the astrocyte promotes oligodendrocyte survival and maturation, and remyelination. Three Specific Aims are proposed. In the first, we will define the effects of IL-11 on oligodendrocytes, and the signaling pathways involved. In the second, we will determine the mechanism underlying the effects of IL-11 on myelin formation. In the third Aim, we will test for an association between IL-11 expression and oligodendrocyte preservation and remyelination in MS lesions. The experiments proposed in this application complement and parallel ongoing work in our laboratory using animal models, and the long-term goal of this work will be to identify novel therapeutic avenues to potentiate oligodendrocyte protection and myelin repair in the MS lesion. Current treatments for multiple sclerosis (MS) aim to reduce the incidence and severity of new lesion formation and clinical relapses, but to date have demonstrated little beneficial effect in terms of promoting regeneration and remyelination. Using a functional genomics-based approach, we have identified the gp130 cytokine interleukin-11 (IL-11) as an astrocyte-derived factor that has supportive effects on oligodendrocytes, and in this proposal we will test the hypothesis that cytokine-induced astrocytic expression of IL-11 potentiates oligodendrocyte survival and maturation, and remyelination, in the MS lesion. The long-term goal of this work will be to identify novel therapeutic avenues for potentiating oligodendrocyte protection and myelin repair in the context of inflammatory CNS demyelinating disease, the significance of which relates to improving the remyelinating capacity of the MS lesion. Current treatments for multiple sclerosis (MS) aim to reduce the incidence and severity of new lesion
formation and clinical relapses, but to date have demonstrated little beneficial effect in terms of promoting
regeneration and remyelination. Using a functional genomics-based approach, we have identified the gp130
cytokine interleukin-11 (IL-11) as an astrocyte-derived factor that has supportive effects on oligodendrocytes,
and in this proposal we will test the hypothesis that cytokine-induced astrocytic expression of IL-11 potentiates
oligodendrocyte survival and maturation, and remyelination, in the MS lesion. The long-term goal of this work
will be to identify novel therapeutic avenues for potentiating oligodendrocyte protection and myelin repair in the
context of inflammatory CNS demyelinating disease, the significance of which relates to improving the
remyelinating capacity of the MS lesion.
描述(申请人提供):调节少突胶质细胞存活和髓鞘形成的机制是多发性硬化(MS)病变修复研究的重点。脱髓鞘和少突胶质细胞损失是该疾病的病理标志,尽管在早期病变中经常观察到少突胶质细胞数量增加和髓鞘再生,但很明显,随着MS的进展,髓鞘再生逐渐失败。目前MS的治疗旨在降低新病变形成和临床复发的发生率和严重程度,但迄今为止,这些方法对再生和髓鞘再生的有益作用很少。因此,髓鞘修复和神经保护仍然是MS研究的主要目标。越来越多的证据表明,介质产生的地方发挥了重要作用,在确定修复MS斑块的成功或失败,和理解髓鞘再生的关键,因此可能在于病变环境的分子研究。反应性星形胶质细胞代表MS斑块中最丰富的细胞组分,并且已经被认为是CNS炎症和再生的调节剂。我们已经研究了星形胶质细胞的反应性和损伤修复之间的潜在联系,使用微阵列分析的阿托伐他汀处理的人星形胶质细胞,这种方法已确定白细胞介素-11(IL-11)作为星形胶质细胞衍生因子,调节少突胶质细胞的存活和成熟,髓鞘形成。通过用已知在MS斑块中表达的细胞因子处理,在人星形胶质细胞培养物中诱导IL-11。在MS组织样品中,IL-11由反应性星形胶质细胞表达,其中表达特别定位于活动性和静止性病变两者的含髓鞘边界。其受体IL-11 R α由少突胶质细胞表达。在人类体外培养中,用IL-11处理导致少突胶质细胞数量显著增加,这与少突胶质细胞存活和成熟增强有关。重要的是,我们还发现IL-11治疗与啮齿动物CNS共培养物中髓鞘形成的显著增加相关。此外,从我们的实验室的初步数据表明,IL-11是保护MS的动物模型。在本申请中,我们将测试的假设,即白细胞介素诱导的星形胶质细胞中的IL-11的表达,促进少突胶质细胞的存活和成熟,和髓鞘再生。提出了三个具体目标。首先,我们将确定IL-11对少突胶质细胞的影响,以及所涉及的信号通路。在第二部分中,我们将确定IL-11对髓鞘形成的影响的机制。在第三个目标中,我们将测试MS病变中IL-11表达与少突胶质细胞保存和髓鞘再生之间的关联。在本申请中提出的实验补充和平行正在进行的工作,在我们的实验室使用动物模型,这项工作的长期目标将是确定新的治疗途径,以加强少突胶质细胞的保护和髓鞘修复的MS病变。目前多发性硬化症(MS)的治疗旨在降低新病变形成和临床复发的发生率和严重程度,但迄今为止,在促进再生和髓鞘再生方面几乎没有表现出有益的效果。使用功能基因组学为基础的方法,我们已经确定了gp 130细胞因子白细胞介素-11(IL-11)作为星形胶质细胞衍生因子,对少突胶质细胞具有支持作用,在本提案中,我们将测试的假设,即苦参碱诱导的星形胶质细胞表达IL-11增强少突胶质细胞的存活和成熟,髓鞘再生,在MS病变。这项工作的长期目标将是确定新的治疗途径,以加强少突胶质细胞的保护和髓鞘修复的情况下,炎性中枢神经系统脱髓鞘疾病,其意义涉及到改善髓鞘再生能力的MS病变。目前多发性硬化症(MS)的治疗旨在降低新发病变的发生率和严重程度
形成和临床复发,但迄今为止已经证明在促进
再生和髓鞘再生。使用功能基因组学为基础的方法,我们已经确定了gp 130
细胞因子白细胞介素-11(IL-11)作为对少突胶质细胞具有支持作用的星形胶质细胞衍生因子,
在本研究中,我们将检验这一假设,即苦参碱诱导的星形胶质细胞表达IL-11增强了
少突胶质细胞的存活和成熟,以及髓鞘再生。这项工作的长期目标是
将确定新的治疗途径,加强少突胶质细胞的保护和髓鞘修复,
炎症性CNS脱髓鞘疾病的背景下,其意义涉及改善
MS损伤的髓鞘再生能力。
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)
专利数量(0)
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GARETH R JOHN其他文献
GARETH R JOHN的其他文献
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{{ truncateString('GARETH R JOHN', 18)}}的其他基金
Kruppel-like factor-6 signaling in myelin formation and repair
髓磷脂形成和修复中的 Kruppel 样因子 6 信号传导
- 批准号:
8908062 - 财政年份:2014
- 资助金额:
$ 23.73万 - 项目类别:
Kruppel-like factor-6 signaling in myelin formation and repair
髓磷脂形成和修复中的 Kruppel 样因子 6 信号传导
- 批准号:
9293399 - 财政年份:2014
- 资助金额:
$ 23.73万 - 项目类别:
Kruppel-like factor-6 signaling in myelin formation and repair
髓磷脂形成和修复中的 Kruppel 样因子 6 信号传导
- 批准号:
8818597 - 财政年份:2014
- 资助金额:
$ 23.73万 - 项目类别:
Reactive astrogliosis regulates blood-brain barrier permeability.
反应性星形胶质细胞增生调节血脑屏障的通透性。
- 批准号:
8134347 - 财政年份:2010
- 资助金额:
$ 23.73万 - 项目类别:
Reactive astrogliosis regulates blood-brain barrier permeability.
反应性星形胶质细胞增生调节血脑屏障的通透性。
- 批准号:
8039033 - 财政年份:2010
- 资助金额:
$ 23.73万 - 项目类别:
Reactive astrogliosis regulates blood-brain barrier permeability.
反应性星形胶质细胞增生调节血脑屏障的通透性。
- 批准号:
8720071 - 财政年份:2010
- 资助金额:
$ 23.73万 - 项目类别:
Reactive astrogliosis regulates blood-brain barrier permeability.
反应性星形胶质细胞增生调节血脑屏障的通透性。
- 批准号:
8535219 - 财政年份:2010
- 资助金额:
$ 23.73万 - 项目类别:
Reactive astrocytes control leukocyte and humoral trafficking into the CNS
反应性星形胶质细胞控制白细胞和体液转运至中枢神经系统
- 批准号:
9334935 - 财政年份:2010
- 资助金额:
$ 23.73万 - 项目类别:
Reactive astrogliosis regulates blood-brain barrier permeability.
反应性星形胶质细胞增生调节血脑屏障的通透性。
- 批准号:
8322110 - 财政年份:2010
- 资助金额:
$ 23.73万 - 项目类别:
Reactive astrocytes control leukocyte and humoral trafficking into the CNS
反应性星形胶质细胞控制白细胞和体液转运至中枢神经系统
- 批准号:
8964009 - 财政年份:2010
- 资助金额:
$ 23.73万 - 项目类别:
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