Intrinsic B cell epigenetic regulation of antibody and autoantibody responses by Sirt1
Sirt1 对抗体和自身抗体反应的内在 B 细胞表观遗传调控
基本信息
- 批准号:10335163
- 负责人:
- 金额:$ 47.44万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2013
- 资助国家:美国
- 起止时间:2013-06-14 至 2024-01-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsATAC-seqAddressAftercareAgingAllergensAnimal ModelAntibodiesAntibody ResponseAntigensAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmunityB cell differentiationB-Cell ActivationB-LymphocytesBackBacteriaBiochemistryBiosensorCell physiologyCellular biologyChIP-seqCuesDNA MethylationDNA Modification MethylasesDataDeacetylationDependenceDevelopmentDiabetes MellitusDietary FiberDown-RegulationElementsEpigenetic ProcessGene ActivationGene ExpressionGenesGeneticGenetic Predisposition to DiseaseGenetic RecombinationGenetic TranscriptionGenomeGlucoseGoalsGrantHistone DeacetylaseHistone Deacetylase InhibitorHistone DeacetylationHistone H3HistonesHomeostasisHumanIgG autoantibodiesImageImmunoglobulin Class SwitchingImmunoglobulin Somatic HypermutationImmunoglobulinsIn VitroInbred MRL lpr MiceInternal Ribosome Entry SiteLuciferasesLupusMYB geneMalignant NeoplasmsMediatingMediator of activation proteinMemoryMemory B-LymphocyteMetabolicMicroRNAsModificationMolecularMouse StrainsMusMutateNF-kappa BPatientsPhasePlasma CellsPost-Translational Protein ProcessingPristaneProcessRegulationReporterRestRoleSIRT1 geneSLEB1 geneSignal PathwaySirtuinsSupplementationTestingTherapeuticTranscription CoactivatorTranscription RepressorUSF1 geneUntranslated RNAUp-RegulationVirusVolatile Fatty AcidsWateractivation-induced cytidine deaminaseanimal imagingcell typecofactordemethylationds-DNAepigenetic regulationexperimental studygut microbiotahuman modelhumanized mouseimmunoregulationin vivoinnovationinsightnicotinamide-beta-ribosidenon-histone proteinnovelnovel therapeuticsorgan injuryoverexpressionprogramspromoterresponsesensorsmall moleculestemsystemic autoimmunitytherapeutic targettissue injurytooltranscriptome sequencing
项目摘要
PROJECT SUMMARY
We want to unveil novel fundamental B cell-intrinsic epigenetic mechanisms that maintain B cell homeostasis
and inform B cell processes critical to the antibody response to exogenous antigens (e.g., viruses, bacteria)
and self-antigens (e.g., dsDNA, RNPs in systemic lupus). As we have shown in the first cycle of this grant,
epigenetic mechanisms interact with genetic programs to modulate AID (encoded by AICDA/Aicda) expression,
critical for SHM/CSR. Indeed, Zn2+-dependent Class I, II and IV HDACs promote AID induction and SHM/CSR
in a B cell-intrinsic fashion. AID induction is dampened by Class I, II and IV HDAC inhibitors, such as short-
chain fatty acids produced by gut microbiota via processing of dietary fibers, through upregulation of select
microRNAs that target AICDA/Aicda 3’UTR, leading to abrogation of antibody/autoantibody responses.
Prompted by our most recent and compelling findings on Sirt1, a NAD+-dependent Class III HDAC and
metabolic sensor implicated in aging, cancer and diabetes, we hypothesize that this Sirtuin dampens AID (a
role opposite to that of Class I, II and IV HDACs) in a B cell-intrinsic fashion, and regulation of Sirt1 expression
or activity effectively modulates SHM/CSR and antibody/autoantibody responses. As we contend, high Sirt1
levels/activity would effect homeostatic Aicda silencing in resting B cells, the first phase of a tri-phasic
fluctuation of reciprocal Sirt1 and AID expression, as followed by low Sirt1 and high AID in activated B cells
and back to high Sirt1 to low AID in plasma cells and memory B cells. Sirt1 would modulate AID expression
through a three-prong histone and non-histone protein deacetylation. It would also enforce a B cell-intrinsic
metabolic–epigenetic checkpoint of AID upregulation since Sirt1 cofactor NAD+ integrates metabolic cues.
Our strengths in B cell biology, molecular SHM/CSR mechanisms and autoimmunity, as well as our cutting-
edge epigenetic approaches (ChIP-Seq, methylDNA-Seq and ATAC-Seq), new tools in biochemistry (NAD+
biosensor), genetics (Cd19+/Cre-Ert2Sirt16fl/flRosa26fl-STOP-fl-tdTomato and Cd19+/Cre-Ert2Rosa26fl-STOP-fl-Sirt1-IRES-Gfp mice),
imaging (AicdaCreRosa26fl-STOP-fl-luciferase reporter mice), and animal models of human antibody/autoantibody
responses (humanized NSG/cKitW-41J mice) make us uniquely poised to test our hypotheses. Aim1 addresses
human and mouse B cell differentiation stage-specific regulation of Sirt1 expression and NAD+ levels, and
underlying mechanisms, with focus on transcription activator USF1, transcription repressor c-Myb and
microRNAs targeting Sirt1 3’UTR. Aim 2 addresses B cell Sirt1 role in dampening AICDA/Aicda expression
through genetics and/or compounds/metabolites, and defines underlying H3K4Ac, H3K36Ac, Dnmt1 and NF-
kB deacetylation mechanisms; Aim 3 addresses the inhibition of antibody and autoantibody responses by B
cell Sirt1 and Sirt1 activators, and explores Sirt1 activators as therapeutics in systemic lupus. Our highly
significant and innovative experiments will provide novel mechanistic insights into B cell epigenetics and
immunoregulation, and yield metabolic-epigenetic checkpoint modulators as new therapeutics in autoimmunity.!
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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Paolo Casali其他文献
Paolo Casali的其他文献
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{{ truncateString('Paolo Casali', 18)}}的其他基金
Epigenetics of the autoantibody response in systemic lupus
系统性狼疮自身抗体反应的表观遗传学
- 批准号:
10494251 - 财政年份:2021
- 资助金额:
$ 47.44万 - 项目类别:
Epigenetics of the autoantibody response in systemic lupus
系统性狼疮自身抗体反应的表观遗传学
- 批准号:
10392220 - 财政年份:2021
- 资助金额:
$ 47.44万 - 项目类别:
Epigenetics of the autoantibody response in systemic lupus
系统性狼疮自身抗体反应的表观遗传学
- 批准号:
10681392 - 财政年份:2021
- 资助金额:
$ 47.44万 - 项目类别:
Epigenetic downregulation of the antibody and autoantibody response
抗体和自身抗体反应的表观遗传下调
- 批准号:
9198631 - 财政年份:2014
- 资助金额:
$ 47.44万 - 项目类别:
Epigenetic downregulation of the antibody and autoantibody response
抗体和自身抗体反应的表观遗传下调
- 批准号:
8996116 - 财政年份:2014
- 资助金额:
$ 47.44万 - 项目类别:
Epigenetic downregulation of the antibody and autoantibody response
抗体和自身抗体反应的表观遗传下调
- 批准号:
9205214 - 财政年份:2014
- 资助金额:
$ 47.44万 - 项目类别:
Epigenetic downregulation of the antibody and autoantibody response
抗体和自身抗体反应的表观遗传下调
- 批准号:
8639370 - 财政年份:2014
- 资助金额:
$ 47.44万 - 项目类别:
Epigenetic downregulation of the antibody and autoantibody response
抗体和自身抗体反应的表观遗传下调
- 批准号:
8794403 - 财政年份:2014
- 资助金额:
$ 47.44万 - 项目类别:
Intrinsic B cell epigenetic regulation of antibody and autoantibody responses by Sirt1
Sirt1 对抗体和自身抗体反应的内在 B 细胞表观遗传调控
- 批准号:
10544531 - 财政年份:2013
- 资助金额:
$ 47.44万 - 项目类别:
Epigenetic downregulation of the antibody response and inhibition of autoimmunity
抗体反应的表观遗传下调和自身免疫的抑制
- 批准号:
8658530 - 财政年份:2013
- 资助金额:
$ 47.44万 - 项目类别:
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