Epigenetic downregulation of the antibody and autoantibody response
抗体和自身抗体反应的表观遗传下调
基本信息
- 批准号:9205214
- 负责人:
- 金额:$ 47.32万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2014
- 资助国家:美国
- 起止时间:2014-02-01 至 2019-01-31
- 项目状态:已结题
- 来源:
- 关键词:3&apos Untranslated RegionsAddressAntibodiesAntibody AffinityAntibody ResponseAntibody SuppressionAntigensAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmune ProcessAutoimmunityB-LymphocytesBacteriaBiochemistryBioinformaticsBiological ProcessButyratesCell physiologyCellular biologyChromatinCytokine ReceptorsDNA MethylationDataDown-RegulationEpigenetic ProcessFDA approvedFutureGene SilencingGene TargetingGenerationsGenesGeneticGenetic Predisposition to DiseaseGenetic RecombinationGenetic TranscriptionHistone AcetylationHistone DeacetylaseHistone Deacetylase InhibitorHistonesHumanImmunoglobulin Class SwitchingImmunoglobulin GImmunoglobulin Somatic HypermutationImmunoglobulinsIn VitroInbred BALB C MiceInjuryKnock-inKnock-in MouseKnockout MiceLupusMapsMediatingMethylationMicroRNAsModificationMolecularMolecular BiologyMusMutateNuclearNuclear AntigensOrganPRDM1 genePathogenicityPathway interactionsPatientsPenetrancePlasma CellsPoriferaPost-Translational Protein ProcessingPreventionProcessProductionRegulationResearchRoleSLEB1 geneSLEB2 geneSLEB3 geneSignal TransductionSiteSymptomsSystemic Lupus ErythematosusT-Independent AntigensTNFRSF5 geneTestingTherapeuticTissuesUntranslated RNAUntranslated RegionsUp-RegulationValproic AcidVirusVorinostatchemical propertycrosslinking and immunoprecipitation sequencingdisorder preventionds-DNAhistone modificationimmune functionimmunoregulationin vivoinhibitor/antagonistinnovationinsightkillingslupus prone micemicrobialmicroorganism antigenmutantneoplastic cellnovel therapeuticspathogenplasma cell differentiationpreventprogramspublic health relevanceresponsesoundtargeted treatmenttool
项目摘要
DESCRIPTION (provided by applicant): Epigenetic downregulation of the antibody and autoantibody response Epigenetic marks include DNA methylation, histone modifications and microRNAs. As we have contended, these "interact" with genetic programs to regulate B cell functions, such as class switch DNA recombination (CSR), somatic hypermutation (SHM) and plasma cell differentiation, thereby informing the antibody response. Epigenetic dysregulation can result in aberrant antibody responses to exogenous antigens, such as those on viruses and bacteria, or self-antigens, such as chromatin, histones and dsDNA in lupus. We hypothesize that the epigenetic modulators histone deacetylase (HDAC) inhibitors (HDIs) inhibit the B cell intrinsic functions CSR/SHM and plasma cell differentiation, thereby blunting antibody and autoantibody responses. We further argue that HDIs inhibit these B cell functions by upregulating selected microRNAs, including miR-155, miR-181b and miR-361 to downregulate AID (Aicda gene, critical for CSR/SHM), as well as miR-23b, miR-30a and miR-125 to downregulate Blimp1 (Prdm1 gene, critical for plasma cell differentiation). Our hypotheses uniquely focus on B cells and are supported by our compelling data using purified human and mouse B cells in vitro, and in vivo in normal mice responding to T-dependent and T- independent antigens, and prevention of disease and "treatment" of lupus-prone mice by HDI. Our strengths in B cell biology, molecular CSR/SHM mechanisms and autoimmunity, and our cutting-edge epigenetic tools and approaches make us uniquely poised to test our hypotheses. We will: (Aim 1) analyze the impact of HDIs (valproic acid, butyrate and SAHA) on CSR/SHM and plasma cell differentiation, and on specific T-dependent and T-independent antibody responses in normal C57BL/6 and Balb/c mice and autoantibody responses in lupus-prone MRL/Faslpr/lpr and B6.NZM/Sle1.Sle2.Sle3 mice; (Aim 2) use molecular biology, biochemistry and high-throughput/bioinformatics tools to analyze HDI-mediated upregulation of miR-155, miR-181b, miR-361, miR-23b, miR-30a and miR-125b in B cells through enhanced histone acetylation and transcription of the microRNA "host genes", address downregulation of AID and Blimp1 by these microRNAs, and construct microRNA in vivo targeting maps of Aicda and Prdm1 3'UTRs using Ago HITS-CLIP; (Aim 3) prove the critical role of B cell microRNAs in mediating HDI suppression of antibody and autoantibody responses using a three-prong integrated in vivo approach involving construction of new knockin mice lacking specific microRNA targeting sites in Aicda or Prdm1 3'UTR, B cell conditional Dicer or Drosha KO mice, and mice expressing "sponge" inhibitors specific for miR-155, miR-181b and miR-361 (targeting Aicda) and/or for miR-23b, miR-30a and miR-125b (targeting Prdm1) in B cells. Our proposal is highly innovative and exquisitely translational. It will provide mechanistic insights and future directions in epigenetics and immunoregulation, including the critical role of B cell microRNAs in antibody/autoantibody responses and epigenetic tools as new therapeutics in autoimmunity.
描述(由申请人提供):抗体和自身抗体反应的表观遗传下调表观遗传标记包括DNA甲基化、组蛋白修饰和microRNA。正如我们所主张的,这些“相互作用”与遗传程序,以调节B细胞的功能,如类转换DNA重组(CSR),体细胞超突变(SHM)和浆细胞分化,从而通知抗体反应。表观遗传失调可导致对外源性抗原(如病毒和细菌上的抗原)或自身抗原(如狼疮中的染色质、组蛋白和dsDNA)的异常抗体应答。 我们假设,表观遗传调节剂组蛋白脱乙酰酶(HDAC)抑制剂(HDIs)抑制B细胞的内在功能CSR/SHM和浆细胞分化,从而钝化抗体和自身抗体的反应。我们进一步认为,HDIs通过上调选定的microRNA来抑制这些B细胞功能,包括下调AID(Aicda基因,对CSR/SHM至关重要)的miR-155、miR-181 B b和miR-361,以及下调Blimp 1(Prdm 1基因,对浆细胞分化至关重要)的miR-23 B b、miR-30 a和miR-125。我们的假设独特地集中在B细胞上,并且得到了我们令人信服的数据的支持,这些数据使用了体外纯化的人和小鼠B细胞,以及在正常小鼠体内对T依赖性和T非依赖性抗原的应答,以及通过HDI预防疾病和“治疗”狼疮易感小鼠。 我们在B细胞生物学、分子CSR/SHM机制和自身免疫方面的优势,以及我们尖端的表观遗传学工具和方法,使我们能够独特地检验我们的假设。我们将:(目的1)分析HDI的影响(丙戊酸、丁酸和SAHA)对CSR/SHM和浆细胞分化的影响,以及对正常C57 BL/6和Balb/c小鼠中特异性T依赖性和T非依赖性抗体应答和狼疮易感MRL/Faslpr/lpr和B6.NZM/Sle1.Sle2.Sle3小鼠中自身抗体应答的影响;(目的2)利用分子生物学、生物化学和高通量/生物信息学工具分析HDI介导的miR-155、miR-181 b、miR-361、miR-23 b、miR-30 a和miR-125 B b在B细胞中通过增强组蛋白乙酰化和microRNA“宿主基因”的转录,解决这些microRNA对AID和Blimp 1的下调,并使用Ago HITS-CLIP构建Aicda和Prdm 1 3 'UTR的microRNA体内靶向图谱;(目的3)使用三种方法证明B细胞microRNA在介导抗体和自身抗体应答的HDI抑制中的关键作用。prong整合的体内方法涉及构建在Aicda或Prdm 1 3 'UTR中缺乏特异性microRNA靶向位点的新敲入小鼠、B细胞条件性Dicer或Drosha KO小鼠和表达对miR-155特异性的“海绵”抑制剂的小鼠,B细胞中的miR-181 b和miR-361(靶向Aicda)和/或miR-23 b、miR-30 a和miR-125 b(靶向Prdm 1)。 我们的建议是高度创新和精美的翻译。它将为表观遗传学和免疫调节提供机制见解和未来方向,包括B细胞microRNA在抗体/自身抗体应答中的关键作用和表观遗传学工具作为自身免疫的新疗法。
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:
$ 47.32万 - 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:
$ 47.32万 - 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:
$ 47.32万 - 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:
$ 47.32万 - 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:
$ 47.32万 - 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:
$ 47.32万 - 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:
$ 47.32万 - 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:
10335163 - 财政年份:2013
- 资助金额:
$ 47.32万 - 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:
$ 47.32万 - 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:
$ 47.32万 - 项目类别:
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