A combined computational and experimental approach to the evolution and role of the DNA sequence environment in targeting mutations to antibody V regions
一种结合计算和实验的方法来研究 DNA 序列环境的进化和在抗体 V 区靶向突变中的作用
基本信息
- 批准号:10090262
- 负责人:
- 金额:$ 3.81万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-03-01 至 2020-10-19
- 项目状态:已结题
- 来源:
- 关键词:AffectAllelesAnimal ExperimentsAntibodiesAntibody AffinityAntigensAutoimmunityB lymphoid malignancyB-Cell DevelopmentB-Cell LymphomasB-LymphocytesBiologicalBiologyCell LineChromatinComplementarity Determining RegionsComputer AnalysisComputer ModelsDNADNA SequenceDataDatabasesDevelopmentDiseaseEnvironmentEnzyme ActivationEvaluationEventEvolutionFamilyFeedbackFrequenciesFutureGTP-Binding Protein alpha Subunits, GsGene-ModifiedGenesGoalsHIVHeavy-Chain ImmunoglobulinsHumanHuman Cell LineImmune responseImmunityImmunoglobulin Somatic HypermutationImmunoglobulinsIndividualInfectionInfectious AgentInfluenzaInfluenza HemagglutininKnock-inLeadLocationMachine LearningMalignant NeoplasmsMediatingMedicalMismatch RepairMolecularMusMutateMutationOutcomePatternPlayPolymeraseProcessPublic HealthResearchRisk FactorsRoleSiteSolid NeoplasmStatistical ModelsStomachStructure of germinal center of lymph nodeTechniquesTestingTherapeutic antibodiesTimeTransgenic MiceVaccinesValidationVariantactivation-induced cytidine deaminasebasechromatin modificationdensityexperimental studygenetic varianthuman datain vivoin vivo Modelinnovationneutralizing antibodyrecruitrepair enzymeresponsespatial relationshipvaccine response
项目摘要
Project summary
There is a fundamental gap in our understanding of how mutations are preferentially targeted to the variable
(V) regions of the Immunoglobulin (Ig) loci during somatic hypermutation (SHM). The persistence of this gap
has limited our understanding of the mutagenic mechanisms involving activation-induced deaminase (AID)
in the immune response and in the role of AID in mis-targeting mutations leading to B-cell lymphomas and
other cancers. The long-term goal of the proposed research is to understand the global targeting of
mutations in immunity that are required to protect us from infections. As high-throughput data from human
antibody immune responses became available, it provided us with new opportunities to generate
hypotheses to explain the underlying mechanisms of SHM. We now propose to generate further hypotheses
using computational models applied to additional databases and to validate these hypotheses using cellular
and animal experiments. Our objective is to understand what directs SHM across the many human Ig heavy
chain V-regions. Our central hypothesis is that the V-region SHM process is highly dependent on a DNA
sequence signature(s) that drives mutations in a largely deterministic fashion. This hypothesis is supported
by our preliminary results using human in vivo data from a few human V region genes and has begun to be
validated using independent databases and experiments in human B cell lines. The rationale is that
evaluations of computational data based upon biological mechanisms, together with appropriate biological
experiments, will reveal the key differences between IGHV regions (IGHV 3-23, 4-34, 1-18, 1-02, etc.) that
lead to the dominance of each of those V regions in the responses to medically important antigens. Our
hypothesis will be tested by pursuing two specific aims: 1) identify the extent to which a DNA signature
determines the mutation process in four individual human IGHV genes that are important in disease
responses; 2) examine the relationship between AID hotspots and Polη hotspots across all the other human
V region genes, thus rigorously defining a mutation targeting signature. Both aims will also entail studying
human V region genes and modifications of them in human cell lines and in mice expressing a human V
region to further confirm the signature and identify molecular mechanisms in vivo. Our approach is
innovative because the computational models we are proposing will be mechanistically motivated focusing
on the interaction between AID and Polη hotspots, thus testing molecular mechanisms as opposed to
classic statistical models using whole V region sequences that ignore the underlying biology. In addition, to
focus on mechanisms we will leverage new high-throughput data from human V regions that have not
undergone antigen selection. Our results will be highly relevant to human IgV repertoire analyses from
immune responses that are currently hard to interpret and will help future vaccine and therapeutic antibody
development, as well as help to understand mutations in human malignancies where AID plays a key role.
项目总结
项目成果
期刊论文数量(0)
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