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
基本信息
- 批准号:8658530
- 负责人:
- 金额:$ 28.64万
- 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 2014-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcetylationAddressAffinityAntibodiesAntibody FormationAntigensAutoantibodiesAutoimmune DiseasesAutoimmune ProcessAutoimmunityB-LymphocytesButyratesCD40 LigandCell physiologyCellsCellular biologyChromatinClinical TrialsDNADNA MethylationDataDown-RegulationEpigenetic ProcessFDA approvedFunctional RNAGene SilencingGenerationsGenesGenetic Predisposition to DiseaseGenetic ProgrammingGenetic RecombinationGenetic TranscriptionGenetic VariationHistone AcetylationHistone Deacetylase InhibitorHistonesHumanImmuneImmunoglobulin Class SwitchingImmunoglobulin GImmunoglobulin Somatic HypermutationIn VitroInjuryInsulin-Dependent Diabetes MellitusIslet CellLeadLupusMediatingMessenger RNAMicroRNAsModificationMolecularMonozygotic TwinningMonozygotic twinsMusMutateNatureNuclear AntigensOrganPathway interactionsPatientsPenetrancePhysiologicalPlasma CellsPlayProductionProteinsRNA DegradationResearchRoleSLEB1 geneSLEB2 geneSLEB3 geneSignal Transduction PathwaySiteStagingSystemic Lupus ErythematosusT-Independent AntigensT-bet proteinTNFSF5 geneTestingTherapeuticTimeTissuesTranslationsUp-RegulationValproic AcidVorinostatbasecrosslinkcytokineepigenomeepigenomicsgenome-widehistone modificationhuman DICER1 proteinimmunoregulationinhibiting antibodyinnovationkillingslupus prone micemicrobialnoveloverexpressionpathogenplasma cell differentiationpreventresponsesoundstemtranscription factortumor
项目摘要
DESCRIPTION (provided by applicant): Epigenetic downregulation of the antibody response and inhibition of autoimmunity Epigenetic marks (including histone modifications, DNA methylation and microRNAs) "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, and compound genetic susceptibility to mediate autoimmunity, including systemic lupus (SLE), in which heavily mutated and class-switched (mainly IgG) autoantibodies to nuclear antigens, as secreted by large numbers of plasma cells, produce widespread tissue and organ injury. Prompted by our compelling preliminary findings in human and mouse B cells in vitro, and in normal and lupus-prone mice, we hypothesize that the epigenetic modulators histone deacetylase inhibitors (HDIs) inhibit CSR/SHM, plasma cell differentiation and, therefore, specific antibody and autoantibody responses, and prevent autoimmunity and "cure" mice in an advanced stage of lupus. We also argue that HDIs inhibit antibody and autoantibody responses by upregulating expression of selected microRNAs through enhanced acetylation and transcription of those microRNA host genes. As suggested by our preliminary data, we contend that HDIs upregulate miR-155, miR-181b, miR-93 to downregulate AID (central to CSR/SHM), miR- 146a to downregulate transcription factors Irf5 and (through Stat1) T-bet (important in CSR to IgG2a and lupus), miR-127 and miR-125b to downregulate Blimp1/Xbp1 (critical for plasma cell differentiation). The Casali lab is uniquely poised to test these novel hypotheses, owing to its record of accomplishment in B cell biology, molecular CSR/SHM and autoimmunity over the last 25 years, and the recently established cutting-edge epigenetic approaches. We will analyze the impact of HDIs (valproic acid, butyrate, suberoylanilide hydroxamic acid) on T-dependent and T-independent antibody responses in normal C57BL/6 and Balb/c mice, and autoantibody responses and autoimmunity in lupus-prone MRL/Faslpr/lpr and B6.NZM/Sle1.Sle2.Sle3 mice (Aim 1). We will address the downregulation of AID, Irf5, T-bet, Blimp1 and Xbp1, as targeted by (HDI-mediated) upregulation of miR-155, miR-181b, miR-93, miR-146a, miR-127 and miR-125b through enhanced acetylation of these microRNA "host genes" (Aim 2). Finally, we will define the role of microRNAs in mediating HDI inhibition of autoimmunity using lupus-prone mice lacking Dicer or Drosha in AID+ B cells or lacking microRNA targeting sites in Aicda and Prdm1 mRNAs, and identify genome-wide HDI-susceptible microRNA/target mRNA pairs in lupus mice (Aim 3). Our proposal is highly significant and innovative, as it addresses core epigenetic mechanisms of lupus and will have sustained impact on the fields of epigenetics, immunoregulation and autoimmunity. Finally, it is exquisitely translational, as (at the time when expensive biologics enter clinical trials) it provies a sound mechanistic basis for use of inexpensive and available epigenetic modulators as therapeutics in autoimmune diseases. !
描述(由申请人提供):表观遗传下调抗体反应和抑制自身免疫表观遗传标记(包括组蛋白修饰、DNA甲基化和microRNAs)与遗传程序相互作用,调节B细胞功能,如类开关DNA重组(CSR)、体细胞高突变(SHM)和浆细胞分化,从而通知抗体反应。表观遗传失调可导致异常的抗体反应和复合遗传易感性,以介导包括系统性红斑狼疮(SLE)在内的自身免疫。在SLE中,大量浆细胞分泌的针对核抗原的严重突变和类别转换的自身抗体(主要是Ig G)会引起广泛的组织和器官损伤。根据我们在体外对人类和小鼠B细胞以及在正常和易患狼疮的小鼠中的令人信服的初步发现,我们假设表观遗传调节剂组蛋白脱乙酰酶抑制物(HDI)抑制CSR/SHM、浆细胞分化,从而抑制特异性抗体和自身抗体反应,并防止自身免疫并在狼疮晚期“治愈”小鼠。我们还认为,HDI通过增强这些microRNA宿主基因的乙酰化和转录,上调选定的microRNAs的表达,从而抑制抗体和自身抗体反应。根据我们的初步数据,我们认为HDI上调miR-155、miR-181b、miR-93下调AID(CSR/SHM的中心),miR-146a下调转录因子IRF5和(通过STAT1)T-bet(在CSR中对IgG2a和狼疮起重要作用),miR-127和miR-125b下调Blimp1/XBP1(对浆细胞分化至关重要)。卡萨利实验室在过去25年里在B细胞生物学、分子CSR/SHM和自身免疫方面取得的成就,以及最近建立的尖端表观遗传学方法,使其能够独一无二地准备测试这些新的假说。我们将分析HDIs(丙戊酸、丁酸、异羟肟酸)对正常C57BL/6和Balb/c小鼠T依赖和T非依赖抗体反应的影响,以及对狼疮易感MRL/Faslpr/LPR和B6.NZM/Sle1.Sle2.Sle3小鼠自身抗体反应和自身免疫的影响(目标1)。我们将解决AID、IRF5、T-BET、Blimp1和XBP1的下调,因为(HDI介导)通过增强这些microRNA“宿主基因”的乙酰化上调miR-155、miR-181b、miR-93、miR-146a、miR-127和miR-125b(目标2)。最后,我们将确定microRNAs在利用AID+B细胞中缺乏DICER或DROSHA的狼疮易感小鼠或在Aicda和Prdm1 mRNAs中缺乏microRNA靶点的狼疮易感小鼠的HDI抑制自身免疫中的作用,并在狼疮小鼠中识别全基因组对HDI敏感的microRNA/靶mRNA对(目标3)。我们的建议具有重要意义和创新性,因为它解决了狼疮的核心表观遗传机制,并将在表观遗传学、免疫调节和自身免疫领域产生持续影响。最后,它是精致的翻译,因为(在昂贵的生物制剂进入临床试验的时候)它为使用廉价和可用的表观遗传调节剂作为自身免疫性疾病的治疗药物提供了可靠的机制基础。好了!
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Paolo Casali其他文献
Paolo Casali的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
$ 28.64万 - 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:
$ 28.64万 - 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:
$ 28.64万 - 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:
$ 28.64万 - 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:
$ 28.64万 - 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:
$ 28.64万 - 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:
$ 28.64万 - 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:
$ 28.64万 - 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:
$ 28.64万 - 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:
$ 28.64万 - 项目类别:
相似海外基金
Rational design of rapidly translatable, highly antigenic and novel recombinant immunogens to address deficiencies of current snakebite treatments
合理设计可快速翻译、高抗原性和新型重组免疫原,以解决当前蛇咬伤治疗的缺陷
- 批准号:
MR/S03398X/2 - 财政年份:2024
- 资助金额:
$ 28.64万 - 项目类别:
Fellowship
Re-thinking drug nanocrystals as highly loaded vectors to address key unmet therapeutic challenges
重新思考药物纳米晶体作为高负载载体以解决关键的未满足的治疗挑战
- 批准号:
EP/Y001486/1 - 财政年份:2024
- 资助金额:
$ 28.64万 - 项目类别:
Research Grant
CAREER: FEAST (Food Ecosystems And circularity for Sustainable Transformation) framework to address Hidden Hunger
职业:FEAST(食品生态系统和可持续转型循环)框架解决隐性饥饿
- 批准号:
2338423 - 财政年份:2024
- 资助金额:
$ 28.64万 - 项目类别:
Continuing Grant
Metrology to address ion suppression in multimodal mass spectrometry imaging with application in oncology
计量学解决多模态质谱成像中的离子抑制问题及其在肿瘤学中的应用
- 批准号:
MR/X03657X/1 - 财政年份:2024
- 资助金额:
$ 28.64万 - 项目类别:
Fellowship
CRII: SHF: A Novel Address Translation Architecture for Virtualized Clouds
CRII:SHF:一种用于虚拟化云的新型地址转换架构
- 批准号:
2348066 - 财政年份:2024
- 资助金额:
$ 28.64万 - 项目类别:
Standard Grant
BIORETS: Convergence Research Experiences for Teachers in Synthetic and Systems Biology to Address Challenges in Food, Health, Energy, and Environment
BIORETS:合成和系统生物学教师的融合研究经验,以应对食品、健康、能源和环境方面的挑战
- 批准号:
2341402 - 财政年份:2024
- 资助金额:
$ 28.64万 - 项目类别:
Standard Grant
The Abundance Project: Enhancing Cultural & Green Inclusion in Social Prescribing in Southwest London to Address Ethnic Inequalities in Mental Health
丰富项目:增强文化
- 批准号:
AH/Z505481/1 - 财政年份:2024
- 资助金额:
$ 28.64万 - 项目类别:
Research Grant
ERAMET - Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
ERAMET - 快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10107647 - 财政年份:2024
- 资助金额:
$ 28.64万 - 项目类别:
EU-Funded
Ecosystem for rapid adoption of modelling and simulation METhods to address regulatory needs in the development of orphan and paediatric medicines
快速采用建模和模拟方法的生态系统,以满足孤儿药和儿科药物开发中的监管需求
- 批准号:
10106221 - 财政年份:2024
- 资助金额:
$ 28.64万 - 项目类别:
EU-Funded
Recite: Building Research by Communities to Address Inequities through Expression
背诵:社区开展研究,通过表达解决不平等问题
- 批准号:
AH/Z505341/1 - 财政年份:2024
- 资助金额:
$ 28.64万 - 项目类别:
Research Grant