Mechanisms of retinal degeneration in neuroinflammatory demyelinating diseases
神经炎症性脱髓鞘疾病中视网膜变性的机制
基本信息
- 批准号:10320047
- 负责人:
- 金额:$ 39.04万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAddressAdultAppearanceAtrophicAttenuatedAutoimmuneAxonBiological MarkersBrainCalciumCell DeathCellsChronicClinicalClinical TrialsCytosolDataDemyelinating DiseasesDemyelinationsElectron MicroscopyElectroretinographyExcitatory NeurotoxinsExhibitsExperimental Autoimmune EncephalomyelitisGeneticGliosisGlutamate ReceptorGlutamatesGrantHealthImageImmuneInflammatoryInflammatory ResponseInjectionsKnockout MiceLaboratoriesLateral Geniculate BodyLesionLightLinkLocationMagnetic Resonance ImagingMeasuresMediatingMicrogliaMitochondriaMorphologyMultiple SclerosisMusMyelinNatural regenerationNerve DegenerationNeuronsOligodendrogliaOptic NerveOptical Coherence TomographyOutcomePathologicPeripheralPermeabilityPharmaceutical PreparationsProcessProliferatingPublishingReceptor SignalingRelapseReporterReportingRetinaRetinal DegenerationRetinal Ganglion CellsSeveritiesSeverity of illnessSourceSpinal CordSymptomsSystemT-LymphocyteTestingThinnessTimeTransgenic MiceVentral Posterolateral NucleusVisionVisualVisual evoked cortical potentialVisual system structureWild Type MouseWorkaxon injuryexcitotoxicityexperimental studygray mattermultiple sclerosis patientneuroinflammationneuron lossneuronal cell bodyoligodendrocyte progenitorpreservationpreventreceptor functionreconstructionremyelinationrepairedresponseretinal ganglion cell degenerationstem cellstraffickingwhite matter
项目摘要
An important question in the field of multiple sclerosis (MS) is whether myelin/axonal damage in the white matter facilitates
neuronal cell body loss in the gray matter, or results from two independent processes. Neurodegeneration underlies
progressive decline in MS for which there is no remedy, highlighting the significance of elucidating its mechanisms. To
address this question, we utilized the visual system, where all myelinated axons in the optic nerve arise from retinal ganglion
cells (RGCs). In patients with MS, RGC loss and retinal thinning correlate with whole-brain and gray matter atrophy.
Therefore, visual assessments may be a sensitive biomarker for neurodegeneration. Furthermore, the visual system is being
used to determine the efficacy of new clinical trial drugs to treat MS. Preliminary data presented in this proposal
demonstrate that blocking AMPA-type glutamate receptor (AMPAR) signaling in mature oligodendrocytes (OLs)
prevents axonal damage in the optic nerve and inhibits retinal ganglion cell loss in experimental autoimmune
encephalomyelitis (EAE). Glutamate dysregulation is implicated in multiple sclerosis (MS), but whether excitotoxic
mechanisms specific to OLs contribute to myelin degradation and impact axonal injury has not been explored. Elevated
levels of glutamate are detected prior to the appearance of new T2-visible white matter lesions implicating glutamate as an
important excitotoxin in patients with MS. We previously reported that MOG-reactive T cells provoke microglia to release
glutamate from the system xc- transporter, promoting myelin degradation during autoimmune demyelination. Here, we show
that selective deletion of AMPAR function on mature OLs diminished the clinical symptoms of EAE, attenuated myelin
and axonal loss in the optic nerve, and inhibited RGC loss. Therefore, we hypothesize that reducing AMPAR-signaling
in OLs prevents demyelination and/or promotes remyelination, resulting in preservation of the underlying axon and
its neuronal soma. These studies will utilize inducible OL-specific deletion of AMPARs in chronic and relapsing-remitting
autoimmune inflammatory (EAE) to explore the impact on axon integrity and ultimately RGC health. Effects of deleting
AMPARs on ionotropic glutamate receptor function will be determined by Ca2+ imaging and mechanisms of cell death as
well as changes in proliferation and differentiation that may promote remyelination. Axon viability will be assessed by
confocal 3D reconstruction, electron microscopy, and mitochondrial trafficking and morphology using transgenic mice that
express fluorescent mitochondria. Changes in OL number and maturation state will be tracked with the genetic fluorescent
reporter tdTomato, to determine the fate of newly proliferated OL progenitor cells separately from pre-existing myelin.
Furthermore, pathological assessments of the retina will be evaluated in light of longitudinal functional visual assessments
(visual evoked potentials and electroretinograms) and longitudinal structural visual imaging (optical coherence tomography)
to investigate how inducible deletion of AMPAR function in OLs modulates retinal function at key time points in
demyelinating diseases.
多发性硬化(MS)领域的一个重要问题是白色物质中的髓鞘/轴突损伤是否有助于多发性硬化(MS)的发生。
灰质中的神经元细胞体损失,或由两个独立的过程引起。神经退行性变
进行性下降的MS,没有补救措施,强调阐明其机制的重要性。到
为了解决这个问题,我们利用了视觉系统,其中视神经中的所有有髓轴突都来自视网膜神经节
细胞(RGC)。在MS患者中,RGC丢失和视网膜变薄与全脑和灰质萎缩相关。
因此,视觉评估可能是神经变性的敏感生物标志物。此外,视觉系统正在
用于确定新的临床试验药物治疗MS的疗效。本提案中提供的初步数据
证明阻断成熟少突胶质细胞(OL)中AMPA型谷氨酸受体(AMPAR)信号传导
预防视神经轴突损伤,抑制实验性自身免疫性视网膜神经节细胞丢失
脑脊髓炎(EAE)。谷氨酸失调与多发性硬化(MS)有关,但是否兴奋毒性
OL的特异性机制导致髓鞘降解并影响轴突损伤尚未探索。升高
在新的T2可见白色物质损伤出现之前检测到谷氨酸水平,表明谷氨酸是一种
我们以前报道过MOG反应性T细胞刺激小胶质细胞释放
谷氨酸从系统XC-转运,促进髓鞘降解过程中自身免疫性脱髓鞘。我们发现
选择性缺失成熟OLs上的AMPAR功能可减轻EAE的临床症状,
和视神经轴突损失,并抑制RGC损失。因此,我们假设减少AMPAR信号传导
防止脱髓鞘和/或促进髓鞘再生,从而保护下面的轴突,
它的神经元索马。这些研究将在慢性和复发缓解型患者中利用诱导型OL特异性AMPAR缺失。
自身免疫性炎症(EAE),以探索对轴突完整性和最终RGC健康的影响。删除的影响
AMPAR对离子型谷氨酸受体功能的影响将通过Ca 2+成像和细胞死亡机制来确定,
以及可能促进髓鞘再生的增殖和分化的变化。轴突活力将通过
共聚焦3D重建,电子显微镜,线粒体运输和形态学,使用转基因小鼠,
表达荧光线粒体。OL数量和成熟状态的变化将用遗传荧光标记跟踪。
报告基因tdTomato,以确定新增殖的OL祖细胞与预先存在的髓磷脂分开的命运。
此外,将根据纵向功能视觉评估来评估视网膜的病理评估。
(视觉诱发电位和视网膜电图)和纵向结构视觉成像(光学相干断层扫描)
研究OLs中AMPAR功能的可诱导缺失如何在关键时间点调节视网膜功能,
脱髓鞘疾病
项目成果
期刊论文数量(0)
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Tara Maria DeSilva其他文献
Tara Maria DeSilva的其他文献
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{{ truncateString('Tara Maria DeSilva', 18)}}的其他基金
Mechanisms of retinal degeneration in neuroinflammatory demyelinating diseases
神经炎症性脱髓鞘疾病中视网膜变性的机制
- 批准号:
10544486 - 财政年份:2021
- 资助金额:
$ 39.04万 - 项目类别:
Mechanisms of activity-dependent myelination in the visual system
视觉系统中活动依赖性髓鞘形成的机制
- 批准号:
9295204 - 财政年份:2016
- 资助金额:
$ 39.04万 - 项目类别:
Mechanisms of Activity-Dependent Myelination in the Visual System
视觉系统中活动依赖性髓鞘形成的机制
- 批准号:
8942434 - 财政年份:2015
- 资助金额:
$ 39.04万 - 项目类别:
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