The Role of Myeloid Cell-Specific Ten-Eleven Translocase 2 (TET2) in Regulation of Neuroinflammation
骨髓细胞特异性 10-11 转位酶 2 (TET2) 在神经炎症调节中的作用
基本信息
- 批准号:10378505
- 负责人:
- 金额:$ 3.23万
- 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:2021-04-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAdoptive TransferAggressive Clinical CourseAnimal ModelAnti-Inflammatory AgentsAntigen PresentationAutoimmuneBlocking AntibodiesBloodBone MarrowCD4 Positive T LymphocytesCD86 geneCNS autoimmune diseaseCNS autoimmunityCell physiologyCellsCellular InfiltrationChIP-seqClinicalCytokine ActivationCytosineDNADataDemyelinationsDevelopmentDioxygenasesDiseaseDown-RegulationEnterobacteria phage P1 Cre recombinaseEnzymesEpigenetic ProcessEtiologyExperimental Autoimmune EncephalomyelitisFamilyFlow CytometryFluorescence-Activated Cell SortingFrequenciesGene ExpressionGeneticGenetic Predisposition to DiseaseGenetic TranscriptionGoalsImmunohistochemistryIn VitroInflammationInflammatoryInterleukin-1 betaInterleukin-4Interleukin-6Knock-outLaboratoriesLeadMalignant NeoplasmsMeasuresMediatingMethylationMicroarray AnalysisModificationMultiple SclerosisMultiple Sclerosis LesionsMusMyelinMyelogenousMyeloid Cell ActivationMyeloid CellsNervous System TraumaNeuraxisNucleic Acid Regulatory SequencesOutcomePTPRC genePathogenesisPathologicPathologyPathway interactionsPatientsPeripheral Blood Mononuclear CellPhagocytosisPhenotypePlayPopulationProductionPropertyRegulationReporterResearchRoleSeveritiesSpleenSusceptibility GeneSystemTamoxifenTimeTranscriptTransgenic Micealpha ketoglutaratecentral nervous system demyelinating disorderchemokineconditional knockoutcytokinedemethylationdisabilityexperiencegenetic risk factorinterestloss of function mutationmembermouse modelmultiple sclerosis patientmultiple sclerosis treatmentneuroimmunologyneuroinflammationneuropathologyneurotoxicitynew therapeutic targetnoveloxidationprogrammed cell death ligand 1promotersingle-cell RNA sequencingtherapeutic targettranslocase
项目摘要
PROJECT SUMMARY
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) believed
to be autoimmune in etiology. Analysis of MS lesions, as well as studies in experimental autoimmune
encephalomyelitis (EAE), a murine model of MS, have indicated that myeloid cells are likely a critical component
of the pathogenesis of CNS autoimmunity. Recently, Ten-Eleven Translocase 2 (TET2) was identified as a
genetic susceptibility locus for MS. TET2 is a Fe(III)-, α-ketoglutarate-dependent enzyme that catalyzes the
oxidation of methylated cytosine to 5’-hydroxymethyl cytosine (5hmC) and promotes active demethylation. 5hmC
is a stable epigenetic mark that can either activate or repress gene expression in a cell- and loci-dependent
manner. There is growing evidence that TET2 acts as a negative regulator of myeloid cell activation and function,
promoting a homeostatic or anti-inflammatory cell state. My hypothesis is that TET2 restrains the pro-
inflammatory functions of myeloid cells to limit inflammation, neurological damage, and disability during CNS
autoimmunity. Supporting this hypothesis, TET2 and 5hmC were found to be reduced in peripheral blood
mononuclear cells of MS patients when compared with controls. Preliminary data from our laboratory
demonstrates that the reduction of TET2 and 5hmC in peripheral blood mononuclear cells is recapitulated in
EAE, and that TET2 transcripts and 5hmC content are further reduced in CNS-infiltrating myeloid cells compared
with the periphery. Additionally, adoptive transfer of encephalitogenic Th17 cells into Tet2+/- mice led to an
exacerbated clinical course compared with Tet2+/+ mice. To continue addressing my hypothesis, I will first
examine the impact of TET2 deficiency in myeloid cells on clinical and pathological outcomes of EAE (Aim 1). I
will do this by examining the EAE disease course, pathology, and cellular infiltration in mice where Tet2 is
knocked out specifically in myeloid cells using a Cre/lox genetic system. Additionally, I will identify the targets of
TET2 in CNS-infiltrating myeloid cells, such as the suppression of pro-inflammatory cytokine production and the
conversion of myeloid cells from a pro-inflammatory phenotype to an anti-inflammatory phenotype (Aim 2).
Completion of these aims will contribute to the fields of neuroimmunology and epigenetics by exploring a novel
mechanism of myeloid cell regulation during CNS autoimmunity, and may lead to the discovery of novel myeloid
cell-specific therapeutic targets for the treatment of MS and related disorders.
项目总结
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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Ashley Munie Gardner其他文献
Ashley Munie Gardner的其他文献
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{{ truncateString('Ashley Munie Gardner', 18)}}的其他基金
The Role of Myeloid Cell-Specific Ten-Eleven Translocase 2 (TET2) in Regulation of Neuroinflammation
骨髓细胞特异性 10-11 转位酶 2 (TET2) 在神经炎症调节中的作用
- 批准号:
10228836 - 财政年份:2021
- 资助金额:
$ 3.23万 - 项目类别:
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