The role of microglia in neuromyelitis optica
The role of microglia in neuromyelitis optica
批准号:
10609887
负责人:
VANDA A LENNON
金额:
$38.79万
依托单位:
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
未结题
起止时间:
2020-06-01 至 2025-04-30
关键词:
AblationAddressAffectAgonistAstrocytesAutoimmune DiseasesAutoimmunityAutomobile DrivingBehavioralBindingBlindnessCellsCentral Nervous SystemCessation of lifeCommunicationComplementComplement 3aCoupledDataDemyelinationsDesigner DrugsDevelopmentDiseaseEventEvolutionFunctional disorderFutureGTP-Binding ProteinsGeneticGliosisIgG autoantibodiesImageImmuneImmunoglobulin GImmunosuppressionImpairmentInflammationInflammatoryInfusion proceduresKnockout MiceLesionMediatingMembraneMicrogliaMinocyclineModelingMolecularMorbidity - disease rateMotorMultiple SclerosisMusNatureNerve DegenerationNeuroimmuneNeuromyelitis OpticaNeuronal DysfunctionNeuronal InjuryOptic NerveOutcomeOxidative StressParalysedPathogenesisPathologicPatientsPatternPreventionProcessProductionProteinsProtonsRelapseResearchRoleSecondary toSpinal CordSpinal Cord LesionsTestingTherapeuticTimeaquaporin 4conventional therapydesigner receptors exclusively activated by designer drugsdiphtheria toxin receptorexperienceexperimental studygenetic approachgenetic technologyglial activationimprovedinhibitormonocytemotor disordermotor impairmentmouse modelnervous system disorderneuroinflammationnovelpathogenic autoantibodiespharmacologicpreventreceptorresponseselective expressiontherapeutic targettooltwo-photonvoltagewater channel
中文摘要
视神经肌萎缩症(NMO)是一种严重的,复发性IgG介导的自身免疫性疾病,靶向
中枢神经系统(CNS),诱导视神经的炎症和优先脱髓鞘,
脊髓大多数患者都有严重的损伤。星形胶质细胞特异性IgG自身抗体
水通道蛋白-4(AQP 4)是引起该病的主要病理生理机制。然而,在这方面,
关于IgG结合到免疫球蛋白后驱动NMO损伤进展的机制知之甚少。
星形胶质细胞膜进入中枢神经系统。我们提出的项目将调查潜在的
小胶质细胞(CNS的常驻免疫细胞)对演变中的NMO损伤的贡献。我们有
开发了一个信息丰富的NMO小鼠模型。鞘内输注NMO-IgG。我们的初步
结果显示,显著的运动功能障碍、星形胶质细胞活化和早期小胶质细胞的独特模式,
对星形胶质细胞的研究防止小胶质细胞活性抑制运动发育
功能障碍总之,这些数据清楚地表明星形胶质细胞-小胶质细胞通讯是早期事件
NMO-IgG进入CNS后。
目标1,将研究星形胶质细胞-小胶质细胞串扰的机制;目标2,将评估
小胶质细胞对NMO发病机制的贡献,目标3将利用新的遗传工具来操纵
小胶质细胞活性作为NMO管理的潜在治疗方法。
我们提出的研究代表了第一次尝试调查小胶质细胞的具体贡献
NMO的发病机制。这些结果应该阐明星形胶质细胞-小胶质细胞串扰的重要性,
NMO的基本机制。这项研究不仅将提高对神经免疫的理解,
但将潜在地确定小胶质细胞是NMO治疗相关靶点。
英文摘要
Neuromyelitis optica (NMO) is a severe, relapsing IgG-mediated autoimmune disease targeting the
central nervous system (CNS), inducing inflammation and preferential demyelination of optic nerve and
spinal cord. Most patients experience severe impairments. IgG autoantibodies specific for the astrocytic
aquaporin-4 (AQP4) water channel are the primary cause of the disease pathophysiology. However,
little is known about the mechanisms driving NMO lesion progression following the binding of IgG to the
astrocyte membrane on entering the CNS. Our proposed project will investigate the potential
contribution of microglia, the resident immune cell of the CNS, to the evolving NMO lesion. We have
developed an informative mouse model of NMO. NMO-IgG is infused intrathecally. Our preliminary
results show significant motor dysfunction, astrocyte activation, and a unique pattern of early microglial
convergence on astrocytes. Prevention of microglial activity suppressed development of motor
dysfunction. In sum, these data clearly indicate astrocyte-microglia communication as an early event
after NMO-IgG enters the CNS.
Aim 1, will investigate the mechanisms underlying astrocyte-microglia crosstalk; Aim 2, will assess the
contribution of microglia to NMO pathogenesis, and Aim 3 will utilize novel genetic tools to manipulate
microglial activity as a potential therapeutic approach to NMO management.
The research we propose represents the first attempt to investigate the specific contribution of microglia
to NMO pathogenesis. The results should clarify the importance of astrocyte-microglia crosstalk and its
underlying mechanisms in NMO. The study will not only improve understanding of neuroimmune
interaction in NMO but will potentially establish that microglia are a pertinent target for NMO therapy.
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
DOI:
10.1093/brain/awab394
发表时间:
2022-05-24
期刊:
Brain : a journal of neurology
影响因子:
--
作者:
[]
通讯作者:
A distinctive IgG-mediated pathogenesis for primary progressive multiple sclerosis?
原发性进行性多发性硬化症的独特 IgG 介导发病机制?
DOI:
10.1093/brain/awad107
发表时间:
2023
期刊:
Brain : a journal of neurology
影响因子:
--
作者:
[Guo,Yong, Lennon,VandaA]
通讯作者:
Lennon,VandaA
The role of microglia in neuromyelitis optica
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批准号:9884293
-
项目类别:
-
资助金额:$46.15万
-
财政年份:2020
-
负责人:VANDA A LENNON
-
依托单位:
The role of microglia in neuromyelitis optica
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批准号:10402351
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项目类别:
-
资助金额:$46.15万
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财政年份:2020
-
负责人:VANDA A LENNON
-
依托单位:
Spectrum of Autoimmune Gastrointestinal Dysmotility
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批准号:6913916
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项目类别:
-
资助金额:$33.53万
-
财政年份:2005
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负责人:VANDA A LENNON
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依托单位:
Spectrum of Autoimmune Gastrointestinal Dysmotility
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批准号:7587405
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项目类别:
-
资助金额:$31.15万
-
财政年份:2005
-
负责人:VANDA A LENNON
-
依托单位:
Spectrum of Autoimmune Gastrointestinal Dysmotility
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批准号:7216785
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项目类别:
-
资助金额:$31.79万
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财政年份:2005
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负责人:VANDA A LENNON
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依托单位:
Spectrum of Autoimmune Gastrointestinal Dysmotility
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批准号:7049382
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项目类别:
-
资助金额:$32.74万
-
财政年份:2005
-
负责人:VANDA A LENNON
-
依托单位:
Spectrum of Autoimmune Gastrointestinal Dysmotility
-
批准号:7387427
-
项目类别:
-
资助金额:$31.15万
-
财政年份:2005
-
负责人:VANDA A LENNON
-
依托单位:
IMMUNOBIOLOGY OF AUTOIMMUNITY
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批准号:3407158
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项目类别:
-
资助金额:$21.06万
-
财政年份:1986
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负责人:VANDA A LENNON
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依托单位:
IMMUNOBIOLOGY OF AUTOIMMUNITY
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批准号:3407156
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项目类别:
-
资助金额:$20.53万
-
财政年份:1986
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负责人:VANDA A LENNON
-
依托单位:
IMMUNOBIOLOGY OF AUTOIMMUNITY
-
批准号:3407159
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项目类别:
-
资助金额:$21.39万
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财政年份:1986
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负责人:VANDA A LENNON
-
依托单位:
IMMUNOBIOLOGY OF AUTOIMMUNITY
-
批准号:3407157
-
项目类别:
-
资助金额:$23.49万
-
财政年份:1986
-
负责人:VANDA A LENNON
-
依托单位:
IMMUNOBIOLOGY OF AUTOIMMUNITY
-
批准号:3407155
-
项目类别:
-
资助金额:$18.46万
-
财政年份:1986
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负责人:VANDA A LENNON
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依托单位:
PARANEOPLASTIC AUTOIMMUNITY--CALCIUM CHANNELS
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批准号:2089288
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项目类别:
-
资助金额:$33.22万
-
财政年份:1984
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负责人:VANDA A LENNON
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依托单位:
PARANEOPLASTIC AUTOIMMUNITY--CALCIUM CHANNELS
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批准号:3175169
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项目类别:
-
资助金额:$26.96万
-
财政年份:1984
-
负责人:VANDA A LENNON
-
依托单位:
AUTOIMMUNE PARANEOPLASTIC SYNDROMES
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批准号:3175165
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项目类别:
-
资助金额:$16.26万
-
财政年份:1984
-
负责人:VANDA A LENNON
-
依托单位:
PARANEOPLASTIC AUTOIMMUNITY--CALCIUM CHANNELS
-
批准号:3175162
-
项目类别:
-
资助金额:$21.47万
-
财政年份:1984
-
负责人:VANDA A LENNON
-
依托单位:
PARANEOPLASTIC AUTOIMMUNITY--CALCIUM CHANNELS
-
批准号:2089289
-
项目类别:
-
资助金额:$32.31万
-
财政年份:1984
-
负责人:VANDA A LENNON
-
依托单位:
AUTOIMMUNE PARANEOPLASTIC SYNDROMES
-
批准号:3175166
-
项目类别:
-
资助金额:$15.99万
-
财政年份:1984
-
负责人:VANDA A LENNON
-
依托单位:
AUTOIMMUNE PARANEOPLASTIC SYNDROMES
-
批准号:3175168
-
项目类别:
-
资助金额:$17.12万
-
财政年份:1984
-
负责人:VANDA A LENNON
-
依托单位:
PARANEOPLASTIC AUTOIMMUNITY--CALCIUM CHANNELS
-
批准号:2089287
-
项目类别:
-
资助金额:$31.31万
-
财政年份:1984
-
负责人:VANDA A LENNON
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依托单位:
海外基金