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)是一种常见的致残性疾病的年轻人。尽管有强烈的免疫治疗,
由于人们所知甚少的原因,不断发生着无情的进展。我们的总体假设是
MS病变内的危险/损伤相关分子模式(DAMP)可抑制
通过阻止少突胶质细胞祖细胞(OPCs)和髓鞘前体细胞的成熟,
通过激活TLR2/MyD88通路,将少突胶质细胞转化为髓鞘生成少突胶质细胞。我们有
先前表明,在DAMPs存在下,OPC成熟为髓鞘化少突胶质细胞被阻断,
在组成型TLR2基因敲除小鼠中,尽管存在DAMP,但仍发生完全髓鞘再生。
我们在本申请中的目标是提供令人信服的机制支持,DAMP在体内的功能,
直接靶向少突胶质细胞谱系,并鉴定TLR2/MyD88的小分子拮抗剂
在MS相关临床前模型中促进髓鞘再生的途径。在第一个目标中,我们将比较
在具有TLR2或MyD88的细胞特异性缺失的小鼠中用菌株匹配的野生型
使用慢性铜腙模型的对照。我们将评估TLR2或MyD88缺失对细胞凋亡的影响。
与慢性脱髓鞘相关的组织病理学:小胶质细胞表型、星形胶质细胞增生和星形细胞瘢痕,以及
轴突健康在目标二中,我们将测试TLR2/MyD88通路的药理学拮抗剂的能力,
以促进MS相关临床前模型中的髓鞘再生。使用34种潜在的TLR2/MyD88拮抗剂,
我们在高通量筛选中鉴定了抗肿瘤活性化合物,我们将首先验证这些化合物,
作为TLR2/MyD88拮抗剂的药物,并确定其在TLR2/MyD88途径中的分子靶点。
验证的TLR2/MyD88拮抗剂将在小脑外植体器官型培养物中测试有效性
促进髓鞘再生在小脑移植物中诱导髓鞘再生的化合物随后会移动
用于临床前动物模型的测试。将基于其对髓鞘再生的两种模型进行评估。
在控制条件下固有缺乏髓鞘再生。第一个模型是慢性的,12周,cuprizone,
与传统的6周铜腙模型相比,不能有效地重新髓鞘化。第二种模式是
立体定向局灶性脱髓鞘与MS相关DAMP的添加,其不能再髓鞘化。的
这些模型的价值在于它们与MS中的髓鞘再生失败具有临床相关性。
然后,将更详细地研究这些MS相关临床前模型中的髓鞘再生,以确定其
药理学靶点及其对髓鞘再生组织病理学的影响。我们选择筛选一个图书馆,
活性化合物,以便在我们的临床前模型中具有活性的药物可以向前发展
直接进入II期临床试验。该项目的独特之处在于:1)DAMP信号的识别,
与CNS髓鞘再生相关的TLR2/MyD88通路; 2)使用具有固有的
髓鞘再生失败;和3)从临床前研究到临床研究的明确路径。
!
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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