Microglial impact on remyelination
小胶质细胞对髓鞘再生的影响
基本信息
- 批准号:10357946
- 负责人:
- 金额:$ 48.74万
- 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
- 起止时间:2020-06-15 至 2025-03-31
- 项目状态:未结题
- 来源:
- 关键词:AftercareAnimal ModelAntibodiesAntibody TherapyAutoantibodiesBrainCCL2 geneCellsCerebrospinal FluidChronicClinicalComplementCorpus CallosumCuprizoneDataDemyelinationsExposure toGene Expression ProfileGenesGenetic TranscriptionHumanIGF1 geneImageImmune responseImmunoglobulin GImpairmentIn SituInflammatoryInfusion proceduresInjectionsInjuryInvestigationKnowledgeLesionLysophosphatidylcholinesMediatingMicrogliaMicroinjectionsModelingMonitorMultiple SclerosisMultiple Sclerosis LesionsMyelinNatural regenerationNervous System PhysiologyNervous System TraumaNervous system structureNeuraxisNeurogliaNeurologicOligodendrogliaPathogenicityPharmacologyPlasma CellsProcessProductionRecombinant AntibodyRecoveryRoleSignal PathwaySignal TransductionSliceTestingThalamic structureTimeTissuesToxinVisualizationcentral nervous system demyelinating disordercentral nervous system injuryclinically relevantdisabilityfunctional restorationglycoprotein NMBgray matterin vivoin vivo Modelin vivo imaginginjury and repairinsightintravital imagingmulti-photonmultiple sclerosis patientnovelnovel therapeutic interventionoligodendrocyte precursorpreventremyelinationrepairedresponseselective expressionsingle-cell RNA sequencingtherapy designwhite matter
项目摘要
PROJECT SUMMARY
Enhancing remyelination is a critical strategy for restoring brain function after demyelination in multiple
sclerosis (MS) patients; however, despite concerted efforts, the ability to stimulate remyelination in MS brain
has remained elusive. While signaling pathways that promote oligodendrocyte precursor differentiation have
been identified, the experimental milieux under investigation do not replicate the mechanisms limiting
remyelination following MS-specific inflammatory CNS injuries. The current proposal builds on our new models
of demyelination/remyelination using pathogenic recombinant antibodies (rAbs) generated from MS patients.
Myelin-specific MS rAbs direct complement-mediated demyelination in vivo and ex vivo, all of which
spontaneously repair in association with microglial activation. However, demyelinated explants that are
continuously exposed to myelin-specific MS rAb fail to activate microglia, and oligodendrocyte maturation is
inhibited. Similarly, targeted depletion of microglia following rAb-mediated demyelination blocks
oligodendrocyte maturation preventing active remyelination. Using single cell RNASeq (scRNASeq) on
microglia isolated from remyelinating explants, we identified transcriptionally distinct microglial subsets that are
associated with successful or failed remyelination. Hence, we hypothesize that microglial signals are critical
for oligodendrocyte responses during the transition from early myelinating to actively myelinating
oligodendrocyte, and myelin-specific MS autoantibody modulates these signals to arrest remyelination. To test
our hypothesis, we propose three complementary specific aims. In Aim 1, we will evaluate microglial and
oligodendrocyte responses in in vivo models of MS rAb-mediated demyelination and compare those responses
to those seen in toxin-mediated demyelination. Intrathalamic or corpus callosum injection of myelin-specific MS
rAb plus HC will be performed in conjunction with pharmacologic microglial depletion and chronic
administration of MS rAb to validate the impact of microglial responses on remyelination in the intact nervous
system. Comparable studies will be done following lysolecithin-induced demyelination, which has a very
different time course of microglial activation and remyelination. In Aim 2, we will study the dynamics of
demyelination, microglial responses and oligodendrocyte regeneration in situ using intravital imaging following
cortical demyelination. This real-time analysis of myelin loss, microglial activation and remyelination will be
compared to that seen following cuprizone-mediated demyelination. Finally, in Aim 3, we will investigate the
mechanisms by which microglia impact remyelination using ex vivo cerebellar slices demyelinated with myelin-
specific rAb plus human complement (HC). We will focus on investigating the role of several microglial genes
identified by scRNASeq that are expected to promote or impair remyelination. Normal appearing white matter
and MS lesion tissue with varying degrees of demyelination and remyelination will be evaluated to determine
the abundance and localization of functionally-important microglial subsets. The results of these studies will
provide insights into novel mechanisms controlling remyelination after inflammatory injury. In addition, the
knowledge gained may identify novel therapeutic approaches that will result in clinically-meaningful myelin
repair.
PROJECT SUMMARY
Enhancing remyelination is a critical strategy for restoring brain function after demyelination in multiple
sclerosis (MS) patients; however, despite concerted efforts, the ability to stimulate remyelination in MS brain
has remained elusive. While signaling pathways that promote oligodendrocyte precursor differentiation have
been identified, the experimental milieux under investigation do not replicate the mechanisms limiting
remyelination following MS-specific inflammatory CNS injuries. The current proposal builds on our new models
of demyelination/remyelination using pathogenic recombinant antibodies (rAbs) generated from MS patients.
Myelin-specific MS rAbs direct complement-mediated demyelination in vivo and ex vivo, all of which
spontaneously repair in association with microglial activation. However, demyelinated explants that are
continuously exposed to myelin-specific MS rAb fail to activate microglia, and oligodendrocyte maturation is
inhibited. Similarly, targeted depletion of microglia following rAb-mediated demyelination blocks
oligodendrocyte maturation preventing active remyelination. Using single cell RNASeq (scRNASeq) on
microglia isolated from remyelinating explants, we identified transcriptionally distinct microglial subsets that are
associated with successful or failed remyelination. Hence, we hypothesize that microglial signals are critical
for oligodendrocyte responses during the transition from early myelinating to actively myelinating
oligodendrocyte, and myelin-specific MS autoantibody modulates these signals to arrest remyelination. To test
our hypothesis, we propose three complementary specific aims. In Aim 1, we will evaluate microglial and
oligodendrocyte responses in in vivo models of MS rAb-mediated demyelination and compare those responses
to those seen in toxin-mediated demyelination. Intrathalamic or corpus callosum injection of myelin-specific MS
rAb plus HC will be performed in conjunction with pharmacologic microglial depletion and chronic
administration of MS rAb to validate the impact of microglial responses on remyelination in the intact nervous
system. Comparable studies will be done following lysolecithin-induced demyelination, which has a very
different time course of microglial activation and remyelination. In Aim 2, we will study the dynamics of
demyelination, microglial responses and oligodendrocyte regeneration in situ using intravital imaging following
cortical demyelination. This real-time analysis of myelin loss, microglial activation and remyelination will be
compared to that seen following cuprizone-mediated demyelination. Finally, in Aim 3, we will investigate the
mechanisms by which microglia impact remyelination using ex vivo cerebellar slices demyelinated with myelin-
specific rAb plus human complement (HC). We will focus on investigating the role of several microglial genes
identified by scRNASeq that are expected to promote or impair remyelination. Normal appearing white matter
and MS lesion tissue with varying degrees of demyelination and remyelination will be evaluated to determine
the abundance and localization of functionally-important microglial subsets. The results of these studies will
provide insights into novel mechanisms controlling remyelination after inflammatory injury. In addition, the
knowledge gained may identify novel therapeutic approaches that will result in clinically-meaningful myelin
repair.
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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Jeffrey L Bennett其他文献
Periodic Alternating Nystagmus, Ataxia, and Spasticity: A Unique Presentation of Spastic Paraplegia 7‐Related Hereditary Spastic Paraplegia
周期性交替眼球震颤、共济失调和痉挛:痉挛性截瘫的独特表现 7 相关遗传性痉挛性截瘫
- DOI:
- 发表时间:
2024 - 期刊:
- 影响因子:4
- 作者:
Jordan L Hickman;Marrisa Lafreniere;Jeffrey L Bennett;Emily Forbes;J. Feuerstein - 通讯作者:
J. Feuerstein
Complement inhibition rapidly blocks lesion extension and facilitates remyelination in neuromyelitis optica
- DOI:
10.1186/s40478-025-02019-7 - 发表时间:
2025-06-12 - 期刊:
- 影响因子:5.700
- 作者:
Katherine S Given;Elizabeth G Acker;Wendy B Macklin;Dan Carlin;Gregory P. Owens;Jeffrey L Bennett - 通讯作者:
Jeffrey L Bennett
Jeffrey L Bennett的其他文献
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{{ truncateString('Jeffrey L Bennett', 18)}}的其他基金
In vivo modeling of autoantibody-induced optic neuritis
自身抗体诱导的视神经炎的体内模型
- 批准号:
10429925 - 财政年份:2021
- 资助金额:
$ 48.74万 - 项目类别:
Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis Optica
视神经脊髓炎的体液免疫、星形胶质细胞损伤和脱髓鞘
- 批准号:
9898380 - 财政年份:2018
- 资助金额:
$ 48.74万 - 项目类别:
Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis Optica
视神经脊髓炎的体液免疫、星形胶质细胞损伤和脱髓鞘
- 批准号:
10372070 - 财政年份:2018
- 资助金额:
$ 48.74万 - 项目类别:
Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis Optica
视神经脊髓炎的体液免疫、星形胶质细胞损伤和脱髓鞘
- 批准号:
10132323 - 财政年份:2018
- 资助金额:
$ 48.74万 - 项目类别:
Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis Optica
视神经脊髓炎的体液免疫、星形胶质细胞损伤和脱髓鞘
- 批准号:
8786891 - 财政年份:2013
- 资助金额:
$ 48.74万 - 项目类别:
Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis Optica
视神经脊髓炎的体液免疫、星形胶质细胞损伤和脱髓鞘
- 批准号:
8418576 - 财政年份:2013
- 资助金额:
$ 48.74万 - 项目类别:
Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis Optica
视神经脊髓炎的体液免疫、星形胶质细胞损伤和脱髓鞘
- 批准号:
9198012 - 财政年份:2013
- 资助金额:
$ 48.74万 - 项目类别:
Humoral Immunity, Astrocyte Injury, and Demyelination in Neuromyelitis Optica
视神经脊髓炎的体液免疫、星形胶质细胞损伤和脱髓鞘
- 批准号:
8601080 - 财政年份:2013
- 资助金额:
$ 48.74万 - 项目类别:
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