Damage Associated Molecular Patterns and Regenerative Failure in MS
多发性硬化症中损伤相关的分子模式和再生失败
基本信息
- 批准号:10327692
- 负责人:
- 金额:$ 36.91万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-12-01 至 2023-11-30
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAnimal TestingAstrocytesAxonBiological AssayBiological ModelsCell MaturationCellsChemicalsChronicCicatrixClinicalClinical ResearchCuprizoneDataDemyelinationsDiseaseEffectivenessExtracellular MatrixFailureFamilyGenerationsGoalsHealthHistopathologyImmunotherapyIndividualInflammatoryInjuryInnate Immune ResponseInstructionKnockout MiceLesionLibrariesMicroscopyModelingModificationMolecularMolecular TargetMultiple SclerosisMultiple Sclerosis LesionsMusMyelinNatural regenerationNerve DegenerationNervous System PhysiologyNeuronsOligodendrogliaPathologic ProcessesPathway interactionsPatternPattern recognition receptorPharmaceutical PreparationsPharmacologyPhasePhenotypePlayPre-Clinical ModelPredispositionRoleSecondary toSignal PathwaySignal TransductionSiteSliceTLR2 geneTestingTissuesToll-like receptorsUrsidae FamilyWorkantagonistastrogliosisbasecell injurychronic demyelinationclinically relevantdisabling diseaseeffectiveness testingexperimental studyextracellularhigh throughput screeningin vivonoveloligodendrocyte lineageoligodendrocyte progenitorpre-clinicalpreclinical studypreventreceptorrecruitregenerativeremyelinationresponsesmall moleculestem cellstissue injuryyoung adult
项目摘要
Multiple Sclerosis (MS) is a common disabling disease of young adults. Despite intense immune therapies,
relentless progression continues to occur for reasons that are poorly understood. Our overall hypothesis is
that Danger/Damage Associated Molecular Patterns (DAMPs) within MS lesions function to inhibit
remyelination by preventing the maturation of both oligodendrocyte progenitor cells (OPCs) and premyelinating
oligodendrocytes into myelinating oligodendrocytes through activation of the TLR2/MyD88 pathway. We have
previously shown that in the presence of DAMPs OPC maturation into myelinating oligodendrocytes is blocked
and that in constitutive TLR2 knock-out mice, complete remyelination occurs despite the presence of DAMPs.
Our objectives in this application are to provide convincing mechanistic support that DAMPs function in vivo by
directly targeting the oligodendrocyte lineage and to identify small molecule antagonists to the TLR2/MyD88
pathway that promote remyelination in MS relevant preclinical models. In the first aim we will compare
remyelination in mice harboring cell specific deletions of either TLR2 or MyD88 with strain matched wild-type
controls using the chronic cuprizone model. We will assess the impact of TLR2 or MyD88 deletion on the
histopathology relevant to chronic demyelination: microglial phenotype, astrogliosis and astrocytic scar, and
axonal health. In aim two we will test pharmacologic antagonists to the TLR2/MyD88 pathway for their ability
to promote remyelination in MS relevant preclinical models. Using 34 potential TLR2/MyD88 antagonists that
we identified in a high throughput screen of pharmacologically active compounds, we will first validate these
agents as TLR2/MyD88 antagonists and determine their molecular target in the TLR2/MyD88 pathway.
Validated TLR2/MyD88 antagonists will be tested in cerebellar explant organotypic cultures for effectiveness
on promoting remyelination. Compounds that induce remyelination in cerebellar explants will then move
forward for testing in preclinical animal models. Two models of remyelination will be assessed based on their
inherent lack of remyelination under control conditions. The first model is chronic, 12 week, cuprizone, which
fails to effectively remyelinate in contrast to the traditional 6-week cuprizone model. The second model is
stereotactic focal demyelination with the addition of an MS relevant DAMP, which fails to remyelinate. The
value of these models is that they bear clinical relevance to remyelinative failure in MS. Drugs that promote
remyelination in these MS relevant preclinical models will then be investigated in greater detail for their
pharmacologic targets and their impact on the histopathology of remyelination. We chose to screen a library of
pharmacologically active compounds such that agents active in our preclinical models can move forward
directly to phase II clinical trail. The unique features of this project are: 1) identification of DAMP signaling and
the TLR2/MyD88 pathway as relevant to CNS remyelination; 2) the use of preclinical models that have inherent
remyelinative failure; and 3) a clear path forward from preclinical studies to clinical research.
!
多发性硬化症(MS)是年轻人常见的致残疾病。尽管有强烈的免疫疗法,
项目成果
期刊论文数量(2)
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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TIMOTHY VARTANIAN其他文献
TIMOTHY VARTANIAN的其他文献
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{{ truncateString('TIMOTHY VARTANIAN', 18)}}的其他基金
Immune Privilege, CNS Autoimmunity, and Clostridium perfringens Epsilon Toxin
免疫特权、中枢神经系统自身免疫和产气荚膜梭菌 Epsilon 毒素
- 批准号:
10754021 - 财政年份:2023
- 资助金额:
$ 36.91万 - 项目类别:
Determining Enhanced Inflammatory B cell Function in African Americans with MS
确定患有多发性硬化症的非裔美国人中增强的炎症 B 细胞功能
- 批准号:
9896484 - 财政年份:2020
- 资助金额:
$ 36.91万 - 项目类别:
Determining Enhanced Inflammatory B cell Function in African Americans with MS
确定患有多发性硬化症的非裔美国人中增强的炎症 B 细胞功能
- 批准号:
10088395 - 财政年份:2020
- 资助金额:
$ 36.91万 - 项目类别:
Damage Associated Molecular Patterns and Regenerative Failure in MS
多发性硬化症中损伤相关的分子模式和再生失败
- 批准号:
10066376 - 财政年份:2017
- 资助金额:
$ 36.91万 - 项目类别:
Innate Immune Mechanisms of Motor Neuron Injury
运动神经元损伤的先天免疫机制
- 批准号:
7860441 - 财政年份:2009
- 资助金额:
$ 36.91万 - 项目类别:
Functional Link Between Innate Immunity, Oligodendrocyte Development, and Myelina
先天免疫、少突胶质细胞发育和髓鞘之间的功能联系
- 批准号:
7698962 - 财政年份:2009
- 资助金额:
$ 36.91万 - 项目类别:
Targeting innate immunity to prevent CNS injury in neonatal meningitis
针对先天免疫预防新生儿脑膜炎中枢神经系统损伤
- 批准号:
7133794 - 财政年份:2006
- 资助金额:
$ 36.91万 - 项目类别:
Targeting innate immunity to prevent CNS injury in neonatal meningitis
针对先天免疫预防新生儿脑膜炎中枢神经系统损伤
- 批准号:
7244141 - 财政年份:2006
- 资助金额:
$ 36.91万 - 项目类别:
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