Autoimmunity risk alleles compromising B cell anergy
损害 B 细胞无反应性的自身免疫风险等位基因
基本信息
- 批准号:9121221
- 负责人:
- 金额:$ 45.51万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-03-01 至 2021-02-28
- 项目状态:已结题
- 来源:
- 关键词:AcuteAffectAllelesAntigen ReceptorsAntigensAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmunityB-Cell ActivationB-LymphocytesCellsChromatinComplementConstitutionDevelopmentDiseaseEnvironmental Risk FactorFeedbackFingerprintFutureGene DeletionGene ProteinsGenesGeneticGenetic ModelsGenetic PolymorphismGenetic Predisposition to DiseaseGenetic VariationGlomerulonephritisGoalsHot SpotHumanImmune ToleranceImmunoglobulin Class SwitchingIndividualInfectionInheritedInjuryInositolLYN geneLeadLife StyleLipidsLupusMaintenanceMediatingMedicalModelingMolecularMonitorMusPTEN genePTPN22 genePTPN6 genePathologyPathway interactionsPatientsPeripheralPhosphoric Monoester HydrolasesPhosphorylationPredispositionPreventionProductionProtein Tyrosine PhosphataseProteinsProto-Oncogene Proteins c-aktRNA InterferenceReceptor SignalingRegulationRegulatory PathwayReportingRequest for ApplicationsResearchRiskRoleSignal PathwaySignal TransductionSiteSpecificitySystemic Lupus ErythematosusTestingTherapeuticTranslatingTyrosine PhosphorylationWorkanergyautoreactive B cellcentral tolerancedisorder riskgene functiongenetic variantin vivoinsightkinase inhibitorknock-downmicrobiomemimeticsnew therapeutic targetpersonalized approachpreventprotein functionrelease of sequestered calcium ion into cytoplasmresponserisk variant
项目摘要
Autoimmunity is caused by conspiring effects of genetic predisposition and environmental factors such as
injury, infection and microbiome constitution. While multiple genetic loci affect susceptibility, in most cases
each in isolation has only a small effect, suggesting that disease develops only when multiple risk-conferring
alleles that function in concert are inherited by a single individual. We hypothesize that such a situation exists
in autoreactive B cells where multiple SLE risk alleles encode molecules that appear to function in signaling
pathways that function normally to limit/terminate antigen receptor signaling. In this application we propose to
test this hypothesis, analyzing the functional interplay of this set of genes/protein and their risk conferring
alleles. Future development and implementation of “precision” medical approaches for treatment of
autoimmunity will require an understanding of the mechanisms by which genetic variations conspire to
increase disease risk, and research proposed here represents a critical first step to enable these efforts.
A number of autoimmunity risk alleles encode molecules previously proposed to function as intermediaries in
signaling pathways involved in regulation of B cell activation. As such they may be important in keeping
autoreactive B cells from becoming activated and contributing to autoimmunity. In this application we request
support to define the functions and functional interactions of proteins encoded by six genes, variants of which
confer increased risk of autoimmunity. Previous reports indicate that B cell-targeted deletion of genes encoding
SHIP-1, PTEN, SHP-1 or LYN, expression of PTPN22 (PEP-R619W), or increased expression of CSK,
promote the development of autoimmunity. However the mechanism by which this occurs is unknown. We
hypothesize that these proteins function as intermediaries in a bifurcating pathway in which final effectors are
the inositol lipid phosphatases SHIP-1 and the tyrosine phosphatase SHP-1. Further, we suggest that both
terminal effectors are required for maintenance of antigen unresponsiveness of anergic B cells. The studies will
employ reductionist genetic models in which risk allele mimetic changes in expression/function of the proteins
can be induced acutely in anergic B cells, and subsequent cell activation, proliferation, differentiation and
autoantibody production monitored. Aim 1 will test the hypothesis that PTPN22, CSK and LYN act in linear
pathways upstream of SHIP-1 and SHP-1, and that genetic variations that confer risk compromise anergy by
undermining their regulatory function. Aim 2 will define the downstream consequences of acute introduction of
risk allele mimetic conditions in terms of development of autoimmune disease, and will test candidate
therapeutic kinase inhibitors. Aim 3 will translate findings, examining the role of SHIP-1 and SHP-1
phosphatases in maintenance anergy of human B cells. Proposed studies will provide important new insight
regarding the in vivo lifestyle of autoreactive B cells whose anergy is compromised by autoimmunity risk alleles.
自身免疫是遗传易感性和环境因素共同作用的结果
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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John C Cambier其他文献
Src-family kinases in B-cell development and signaling
B 细胞发育和信号转导中的 Src 家族激酶
- DOI:
10.1038/sj.onc.1208075 - 发表时间:
2004-10-18 - 期刊:
- 影响因子:7.300
- 作者:
Stephen B Gauld;John C Cambier - 通讯作者:
John C Cambier
John C Cambier的其他文献
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{{ truncateString('John C Cambier', 18)}}的其他基金
Autoimmunity risk alleles compromising B cell anergy
损害 B 细胞无反应性的自身免疫风险等位基因
- 批准号:
9568080 - 财政年份:2016
- 资助金额:
$ 45.51万 - 项目类别:
Insulin Specific T and B cells in Type 1 Diabetes
1 型糖尿病中的胰岛素特异性 T 细胞和 B 细胞
- 批准号:
9180031 - 财政年份:2016
- 资助金额:
$ 45.51万 - 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
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8282484 - 财政年份:2012
- 资助金额:
$ 45.51万 - 项目类别:
Mouse modeling of a human STING gene variant for infectious disease
人类 STING 基因变体感染性疾病的小鼠模型
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8519291 - 财政年份:2012
- 资助金额:
$ 45.51万 - 项目类别:
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