Low density neutrophils and lupus
低密度中性粒细胞和狼疮
基本信息
- 批准号:10743175
- 负责人:
- 金额:$ 36.25万
- 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:2022-12-08 至 2024-11-30
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAffectAntigen-Antibody ComplexAutoantibodiesAutoimmuneAutoimmune DiseasesB-Cell DevelopmentB-LymphocytesBinding SitesBlood CellsCell LineCellsCharacteristicsChemotaxisChromatinClinicalClinical TrialsCo-ImmunoprecipitationsComplexCytokine SignalingDNA-Binding ProteinsDataDendritic CellsDevelopmentDiseaseEpigenetic ProcessExhibitsGene ExpressionGene Expression ProfileGenesGeneticGenetic TranscriptionGoalsGrowth FactorHeterogeneityHuman Herpesvirus 4Immune responseImpairmentIndividualInflammatoryInterferon alphaKidneyKnowledgeLaboratoriesLupusMaintenanceMass Spectrum AnalysisMediatorMicroRNAsPathogenesisPathogenicityPathway interactionsPatientsPhagocytosisPhenotypePredispositionProductionProteinsPublishingReceptor SignalingRegulatory PathwaySortingSymptomsSystemic Lupus ErythematosusTechnologyTestingTissue-Specific Gene ExpressionTransgenic MiceTreatment ProtocolsValidationbody systemconstitutive expressioncytokinedensitydifferential expressioneffective therapyexperimental studyextracellulargranulocyteindexingindividual patientinhibitorneutrophilnew therapeutic targetnoveloverexpressionpathogenposttranscriptionalprotein expressionsuccesstherapeutic targettranscriptome sequencing
项目摘要
Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease that affects multiple organ systems
and for which current treatments are toxic and impair immune responses to pathogens, so new treatment
regimens are needed. Identification of new therapeutic targets is complicated by a lack of understanding of the
mechanisms that cause SLE. ARID3a is a DNA-binding protein that can alter gene expression both at the
transcription level, and by contributing to epigenetic landscapes. We found that ARID3a protein is expressed in
low density neutrophils (LDNs) of SLE patients, but not in LDNs from healthy controls, and ARID3a expression
was associated with production of the inflammatory cytokine, interferon alpha (IFNα) in the same cells.
Surprisingly, increased numbers of ARID3a+ LDNs are more significantly associated with increased disease
activity indices (SLEDAI scores; R2=0.65) in SLE patients than were numbers of IFNα-producing LDNs. These
data suggest that ARID3a-expressing LDNs contribute to disease activity in SLE through other mechanisms
than IFNα production. Our previous data suggested that ARID3a protein expression was associated with
differential gene expression patterns in LDNs. We hypothesize that ARID3a-associated gene dysregulation
contributes to SLE disease pathogenesis. Therefore, our first aim is to define binding sites for ARID3a near
differentially expressed genes and accessible epigenetic domains in SLE. The second specific aim will directly
test known functions of LDNs to define which of those functions require ARID3a expression and which may be
inhibited with ARID3a-specific inhibitors. Finally, we found that ARID3a expression in LDNs is not regulated at
the level of transcription, perhaps explaining why ARID3a has not been previously identified through elegant
RNA-seq studies as potential driver of pathogenesis in SLE LDNs. Our third aim will determine how ARID3a
protein expression is induced in LDNs. Our published and preliminary data support the idea that ARID3a
contributes to, or is a consequence of, disease activity in SLE and that inhibition of ARID3a decreases
autoimmune symptoms. These experiments will fill important gaps in our understanding of how ARID3a is
associated with SLE and will define functions and genetic pathways that may serve as new therapeutic targets
for this devastating disease.
摘要
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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Carol F Webb其他文献
Carol F Webb的其他文献
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{{ truncateString('Carol F Webb', 18)}}的其他基金
ARID3a, a repressor in aged kidney progenitors?
ARID3a,衰老肾祖细胞的抑制因子?
- 批准号:
10390496 - 财政年份:2022
- 资助金额:
$ 36.25万 - 项目类别:
Identification of Proteins Interacting with ARID3a
与 ARID3a 相互作用的蛋白质的鉴定
- 批准号:
9248234 - 财政年份:2016
- 资助金额:
$ 36.25万 - 项目类别:
Role of the transcription factor ARID3a in lupus
转录因子 ARID3a 在狼疮中的作用
- 批准号:
8074998 - 财政年份:2010
- 资助金额:
$ 36.25万 - 项目类别:
Role of the transcription factor ARID3a in lupus
转录因子 ARID3a 在狼疮中的作用
- 批准号:
7976566 - 财政年份:2010
- 资助金额:
$ 36.25万 - 项目类别:
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