The role of ion channels and transporters in B cell function
离子通道和转运蛋白在 B 细胞功能中的作用
基本信息
- 批准号:10620690
- 负责人:
- 金额:$ 5.27万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-07-17 至 2025-07-16
- 项目状态:未结题
- 来源:
- 关键词:2019-nCoVAcidityAddressAdoptive TransferAdverse effectsAffectAntibodiesAntibody-Producing CellsAntibody-mediated protectionAntigensApoptoticAttenuatedAutoantibodiesAutoimmune DiseasesAutophagocytosisB cell therapyB-Cell ActivationB-Cell Acute Lymphoblastic LeukemiaB-Cell DevelopmentB-Lymphocyte SubsetsB-LymphocytesBicarbonatesBiological ProductsCRISPR screenCardiovascular DiseasesCell CompartmentationCell physiologyCellsCellular biologyClinicalClustered Regularly Interspaced Short Palindromic RepeatsCoupledDefectDiseaseDrug TargetingErythrocytesExperimental Autoimmune EncephalomyelitisGenesGenetic ScreeningGuide RNAHematopoietic stem cellsHumoral ImmunitiesImmuneImmune System DiseasesImmune responseImmunizeImmunoglobulin Class SwitchingImmunoglobulin Switch RecombinationImmunology procedureImpairmentIn VitroInfectionInfluenzaInfluenza A virusIon ChannelIon TransportIonsLipid BilayersMS4A1 geneMature B-LymphocyteMeasuresMediatingMediatorMembrane ProteinsMetabolicModelingMolecularMolecular TargetMonoclonal AntibodiesMultiple SclerosisMusNeurologyOutcomePRDM1 genePathogenesisPathologicPathway interactionsPeripheralPhysiologicalPlasma CellsPlayPopulation HeterogeneityProductionProliferatingProteinsRegulationRoleSeveritiesSheepSignal PathwaySignal TransductionSpecificitySystemTestingVaccinesValidationViralViral PhysiologyVirus Diseasesantiviral immunitycell typedruggable targetextracellularforward geneticsfunctional genomicshumoral immunity deficiencyimmunoregulationin vivoinfluenza infectioninfluenza virus strainmRNA Expressionmammalian genomemouse modelneutralizing antibodynew therapeutic targetnovelnovel drug classoligodendrocyte-myelin glycoproteinpharmacologicplasma cell differentiationreconstitutionresponseretroviral transductionrituximabside effectsmall moleculesymportertositumomabtranscriptome sequencingtranscriptomicsvirtual
项目摘要
PROJECT SUMMARY/ABSTRACT
B cells are a central player in the humoral immune response, which is elicited by differentiated, antibody-
producing B cell-types known as plasma cells (PCs). During viral infections such as influenza or SARS-CoV2,
PCs produce antibodies that neutralize viral activity. Furthermore, PCs have been implicated in the pathogenesis
of many autoimmune diseases, including multiple sclerosis (MS). Thus, the capacity to modulate B cell function,
notably PC differentiation and activity, has broad clinical implications. The leading therapy for specific regulation
of B cell function is a monoclonal antibody targeting CD20, leading to brash depletion of virtually all B cell subsets
and resulting in various side effects. Thus, there is a clinical need for molecular targets that affect B cell function
in more refined and precise manners.
Ion channels and transporters (ICTs) mediate the flux of ions across the lipid bilayer, which can further regulate
intracellular signaling. ICTs are desirable clinical targets because 1) many are surface proteins accessible to
biologics and 2) multiple small-molecule ICT modulators have already been developed. Unfortunately, though
substantive evidence exists that different ICTs can contribute to different aspects of B function, this intersection
remains poorly investigated. To address this gap, I will leverage transcriptomic analyses and functional
genomics, coupled with experimental validations. Based on an RNA-seq and a CRISPR screen, I came across
SLC4A7, a Na+/HCO3- co-transporter known to regulate intracellular pH. Deletion of SLC4A7 in B cells selectively
impaired PC differentiation in vitro and in vivo. In Aim 1, I will further characterize how SLC4A7 affects PC
differentiation signaling pathways, intracellular pH, and the autophagy pathway. In Aim 2, I will determine how
deletion of SLC4A7 in B cells affects the immune response against influenza infection as well as the
pathogenesis of a murine model for MS. Overall, this project will elucidate novel mechanisms by which
intracellular pH regulates PC differentiation and reveal a novel target (SLC4A7) with which B cell function
can be modulated, especially in the context of MS.
项目总结/文摘
项目成果
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