The role of N6-methyladenosine RNA modification in programmed and aberrant DNA mutagenesis in B cells
N6-甲基腺苷 RNA 修饰在 B 细胞程序性和异常 DNA 突变中的作用
基本信息
- 批准号:10721410
- 负责人:
- 金额:$ 5.31万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-09-09 至 2024-08-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAntibodiesAntibody AffinityAntigensAutomobile DrivingB lymphoid malignancyB-Cell DevelopmentB-LymphocytesBiochemistryBiological AssayBiologyBone MarrowCD19 geneCell LineCell LineageCell physiologyChromatinChromosomal InstabilityChromosome abnormalityCodeComplexCorrelative StudyCoupledDNADNA Double Strand BreakDNA Sequence AlterationDNA Single Strand BreakDNA StructureDataDefectDiseaseEnzymesEvaluationEventFrequenciesGene ActivationGene ExpressionGene RearrangementGenerationsGenesGenetic RecombinationGenetic TranscriptionGenomeGenome StabilityGenomic InstabilityGenomicsGoalsHeavy-Chain ImmunoglobulinsHematopoiesisHeterodimerizationIGH@ gene clusterIgG1Immune System DiseasesImmunizeImmunoglobulin AImmunoglobulin Class SwitchingImmunoglobulin GenesImmunoglobulin Somatic HypermutationImmunoglobulin Switch RecombinationImmunoglobulinsLaboratoriesLight-Chain ImmunoglobulinsLoxP-flanked alleleLymphoidLymphomagenesisMature B-LymphocyteMediatingMethylationMicroscopyModificationMolecularMultiple MyelomaMusMutagenesisMutationPathway interactionsPeyer&aposs PatchesPlayPost-Transcriptional RNA ProcessingPost-Transcriptional RegulationPreventionProcessProductionPropertyProteinsRNARNA DegradationRNA ProcessingRNA methylationRag1 MouseResearch DesignResolutionRestRoleSingle-Stranded DNASiteSomatic MutationSterilityStructureStructure of germinal center of lymph nodeSystemTranscriptUntranslated RNAV(D)J Recombinationactivation-induced cytidine deaminaseadaptive immune responsecancer cellcellular developmentds-DNAepigenomicsexosomeexperimental studygenome integrityhumoral immunity deficiencyin vivolarge cell Diffuse non-Hodgkin&aposs lymphomaleukemia/lymphomamouse geneticsmouse modelmutantposttranscriptionalpreventprogenitorrecruitsingle moleculesuperresolution microscopytranscriptome sequencing
项目摘要
PROJECT SUMMARY
Background: VDJ recombination, Class switch recombination (CSR) and somatic hypermutation (SHM) are
three B lymphocyte specific processes that mediate antibody gene diversification. VDJ recombination requires
the DNA double strand generation by the Recombination activation genes (RAG1 an RAG2) where as CSR and
SHM requires the single-strand DNA break activity of the Activation Induced Deaminase (AID) enzyme. Both
RAG1/2 and AID activities are coupled with noncoding RNA transcription at sites of DNA break/mutation. The
properties of the ncRNAs generated at sites of programmed DNA breaks are poorly characterized in B cells.
Recently advances in biology has provided compelling evidence that post-transcriptional and co-transcriptional
modification of ncRNAs determine a component of RNA epigenomics and have significant role in driving
cellular development and function. In this application, supported by preliminary data generated in our
laboratory, we are evaluating the role of RNA modification N6-methyladenosine (m6A) and its associated
enzymes METTL3 and METTL14 in B cell development, function and genomic integrity.
Objective/Hypothesis: In his proposal, we will determine how RNA methylation m6A on transcripts
generated in the IgH locus and the rest of the B cell genome controls programmed DNA recombination,
antibody gene diversification and prevents chromosomal instability.
Specific Aims: Aim 1: Aim 1: Are m6A modifying enzymes Mettl3 and Mettl14 important for class switch
recombination, somatic hypermutation, and/or for preventing genomic stability in B cells? ; AIM 2: What is the
mechanism by which m6A modification promotes IgH DNA recombination and/or prevents genomic
instability? AIM 3: Do RNA methylation and coupled RNA surveillance pathways have a role in early B cell
development and during VDJ recombination?
Study Design: Using cell lines and mouse models, we will study mechanism by which RNA m6A methylation
plays a role in programmed DNA recombination and protection of B cell genomic integrity. We will evaluate
the mechanism of formation of single-strand DNA structures formation and RNA surveillance at sites of AID
activity in matured B cells and the mechanism by which inhibitory RNAs are degraded at sites of RAG activity
in B cells during VDJ recombination. We will also evaluate the molecular mechanism by which RNA
modification promotes programmed DNA rearrangements. We use a combination of mouse genetics, genomics,
biochemistry and 3D-STORM microscopy to accomplish the goals of the proposed project.
Disease Relevance: B cells are a central component of the adaptive immune response, but also prone to
undergo leukemias and lymphomas when antibody gene diversification processes are not well controlled.
Proposed studies leads to a better understanding of the mechanism of antibody gene diversification but also
educate us how B cell cancer (specially in context of DLBCL and Multiple Myeloma) are prevented.
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)
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 }}
Uttiya Basu其他文献
Uttiya Basu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('Uttiya Basu', 18)}}的其他基金
FASEB's "The RNA Associated Mechanisms Conference: In Immunity and Disease"
FASEB 的“RNA 相关机制会议:免疫与疾病”
- 批准号:
9993686 - 财政年份:2021
- 资助金额:
$ 5.31万 - 项目类别:
The role of N6-methyladenosine RNA modification in programmed and aberrant DNA mutagenesis in B cells
N6-甲基腺苷 RNA 修饰在 B 细胞程序性和异常 DNA 突变中的作用
- 批准号:
10461710 - 财政年份:2020
- 资助金额:
$ 5.31万 - 项目类别:
The role of N6-methyladenosine RNA modification in programmed and aberrant DNA mutagenesis in B cells
N6-甲基腺苷 RNA 修饰在 B 细胞程序性和异常 DNA 突变中的作用
- 批准号:
9897023 - 财政年份:2020
- 资助金额:
$ 5.31万 - 项目类别:
The role of N6-methyladenosine RNA modification in programmed and aberrant DNA mutagenesis in B cells
N6-甲基腺苷 RNA 修饰在 B 细胞程序性和异常 DNA 突变中的作用
- 批准号:
10259665 - 财政年份:2020
- 资助金额:
$ 5.31万 - 项目类别:
The role of N6-methyladenosine RNA modification in programmed and aberrant DNA mutagenesis in B cells
N6-甲基腺苷 RNA 修饰在 B 细胞程序性和异常 DNA 突变中的作用
- 批准号:
10598241 - 财政年份:2020
- 资助金额:
$ 5.31万 - 项目类别:
The role of N6-methyladenosine RNA modification in programmed and aberrant DNA mutagenesis in B cells
N6-甲基腺苷 RNA 修饰在 B 细胞程序性和异常 DNA 突变中的作用
- 批准号:
10682918 - 财政年份:2020
- 资助金额:
$ 5.31万 - 项目类别:
The role of N6-methyladenosine RNA modification in programmed and aberrant DNA mutagenesis in B cells
N6-甲基腺苷 RNA 修饰在 B 细胞程序性和异常 DNA 突变中的作用
- 批准号:
10683111 - 财政年份:2020
- 资助金额:
$ 5.31万 - 项目类别:
Long noncoding RNA expressing genomic element that control antibody diversification and chromosomal integrity in B cells
表达控制 B 细胞抗体多样化和染色体完整性的基因组元件的长非编码 RNA
- 批准号:
10303057 - 财政年份:2017
- 资助金额:
$ 5.31万 - 项目类别:
Long noncoding RNA expressing genomic elements that control antibody diversification and chromosomal integrity in B cells
表达控制 B 细胞抗体多样化和染色体完整性的基因组元件的长非编码 RNA
- 批准号:
10531294 - 财政年份:2017
- 资助金额:
$ 5.31万 - 项目类别:
Long noncoding RNA expressing genomic element that control antibody diversification and chromosomal integrity in B cells
表达控制 B 细胞抗体多样化和染色体完整性的基因组元件的长非编码 RNA
- 批准号:
10065485 - 财政年份:2017
- 资助金额:
$ 5.31万 - 项目类别:
相似海外基金
University of Aberdeen and Vertebrate Antibodies Limited KTP 23_24 R1
阿伯丁大学和脊椎动物抗体有限公司 KTP 23_24 R1
- 批准号:
10073243 - 财政年份:2024
- 资助金额:
$ 5.31万 - 项目类别:
Knowledge Transfer Partnership
Role of Natural Antibodies and B1 cells in Fibroproliferative Lung Disease
天然抗体和 B1 细胞在纤维增生性肺病中的作用
- 批准号:
10752129 - 财政年份:2024
- 资助金额:
$ 5.31万 - 项目类别:
CAREER: Next-generation protease inhibitor discovery with chemically diversified antibodies
职业:利用化学多样化的抗体发现下一代蛋白酶抑制剂
- 批准号:
2339201 - 财政年份:2024
- 资助金额:
$ 5.31万 - 项目类别:
Continuing Grant
Isolation and characterisation of monoclonal antibodies for the treatment or prevention of antibiotic resistant Acinetobacter baumannii infections
用于治疗或预防抗生素耐药鲍曼不动杆菌感染的单克隆抗体的分离和表征
- 批准号:
MR/Y008693/1 - 财政年份:2024
- 资助金额:
$ 5.31万 - 项目类别:
Research Grant
Developing first-in-class aggregation-specific antibodies for a severe genetic neurological disease
开发针对严重遗传神经系统疾病的一流聚集特异性抗体
- 批准号:
10076445 - 财政年份:2023
- 资助金额:
$ 5.31万 - 项目类别:
Grant for R&D
Discovery of novel nodal antibodies in the central nervous system demyelinating diseases and elucidation of the mechanisms through an optic nerve demyelination model
发现中枢神经系统脱髓鞘疾病中的新型节点抗体并通过视神经脱髓鞘模型阐明其机制
- 批准号:
23K14783 - 财政年份:2023
- 资助金额:
$ 5.31万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
Elucidation of the mechanisms controlling the physicochemical properties and functions of supercharged antibodies and development of their applications
阐明控制超电荷抗体的理化性质和功能的机制及其应用开发
- 批准号:
23KJ0394 - 财政年份:2023
- 资助金额:
$ 5.31万 - 项目类别:
Grant-in-Aid for JSPS Fellows
Role of antibodies in hepatitis E virus infection
抗体在戊型肝炎病毒感染中的作用
- 批准号:
10639161 - 财政年份:2023
- 资助金额:
$ 5.31万 - 项目类别:
Defining the protective or pathologic role of antibodies in Post-Ebola Syndrome
定义抗体在埃博拉后综合症中的保护或病理作用
- 批准号:
10752441 - 财政年份:2023
- 资助金额:
$ 5.31万 - 项目类别:
Human CMV monoclonal antibodies as therapeutics to inhibit virus infection and dissemination
人 CMV 单克隆抗体作为抑制病毒感染和传播的治疗药物
- 批准号:
10867639 - 财政年份:2023
- 资助金额:
$ 5.31万 - 项目类别: