Identification of Specific Roles for Ets-1 in B Cell Tolerance
Identification of Specific Roles for Ets-1 in B Cell Tolerance
批准号:
8651860
负责人:
LEE ANN Garrett-Sinha
金额:
$39.3万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-05-15 至 2016-04-30
关键词:
Adaptor Signaling ProteinAntibodiesAntibody FormationAntigen-Antibody ComplexAutoantibodiesAutoantigensAutoimmune DiseasesAutoimmune ProcessAutoimmune ResponsesB cell differentiationB-LymphocytesBindingBiologicalBiological AssayBlocking AntibodiesBone MarrowCell Differentiation processCell physiologyCellsCuesDNA BindingDNA Binding DomainDNA SequenceDataDefectDevelopmentEnhancersExhibitsGene ExpressionGene TargetingGenesGleanHematopoieticHomeostasisImmune responseImmunoglobulin GImmunoglobulin MImmunoglobulin-Secreting CellsIn VitroInfectionKidney DiseasesKnockout MiceLigandsModelingMolecularMolecular ProfilingMusNuclear AntigensNucleic Acid Regulatory SequencesOrganPathologyPathway interactionsPeripheralPlasma CellsPreventionProcessProductionProteinsReceptor SignalingRegulationRelative (related person)Rheumatoid FactorRoleSerumSignal TransductionT-LymphocyteTLR7 geneTissuesToll-like receptorsTranscriptional RegulationTransgenic MiceTransgenic ModelTransgenic Organismsanergyautoreactive B cellcell typecohortdifferentiated B cellfightingin vitro Assayin vivoinhibiting antibodyinsightmouse modelnovelpathogenpreventpromoterpublic health relevanceresponsetranscription factor
中文摘要
描述(由申请方提供):抗体分泌细胞(ASC)产生抗体对于针对许多不同病原体的免疫应答至关重要。然而,在B细胞耐受性被破坏的自身免疫性疾病中,许多ASC分泌自身抗体并以主要方式促成器官病理学。B细胞向ASC的分化由一组关键转录因子控制,包括Ets-1,其作为该过程的负调节因子。在不存在Ets-1的情况下,B细胞经历增强的分化成ASC,其中许多ASC分泌自身抗体,如血清中IgM和IgG自身抗体的高滴度所证明的。最近,Toll样受体(TLR)信号传导,特别是通过TLR 7和TLR 9,已经涉及自身反应性B细胞的活化以分化成ASC.有趣的是,Ets-1缺陷型B细胞在体外表现出对TLR 7和TLR 9配体的增强的应答,并且缺乏TLR衔接蛋白Myd 88的Ets-1敲除小鼠具有减少的自身抗体产生。Toll样受体信号传导是Blimp-1表达的有效诱导剂,Blimp-1是驱动ASC分化的关键转录因子。Ets-1与Blimp-1物理相互作用以抑制Blimp-1结合靶DNA序列的能力。相反,一个密切相关的转录因子Ets-2不能阻断Blimp-1结合或抑制ASC分化。Ets-1也被认为调节控制ASC形成的关键靶基因的表达,但这些靶基因中的大多数的身份仍不清楚。在本申请中,我们提出了多种测定法来进一步确定Ets-1在调节靶基因表达、Blimp-1活性和ASC分化中的作用。这些研究将通过比较Ets-1的生物活性来帮助,Ets-1可以阻断ASC分化,而Ets-2蛋白缺乏这种活性。该建议的具体目的是(1)确定哪些细胞类型需要Ets-1活性以限制ASC形成、自身抗体分泌和自身免疫疾病,(2)检查TLR 7和9配体在激活Ets-1缺陷型B细胞中的体内作用,(3)鉴定调节ASC形成的Ets-1依赖性基因表达途径和(4)鉴定Ets-1依赖性基因表达途径的结构特征。1,其赋予调节ASC发育的独特能力。我们的研究将为B细胞分化的转录调控提供新的见解,特别是在自身抗体分泌的情况下。
英文摘要
DESCRIPTION (provided by applicant): The production of antibodies by antibody-secreting cells (ASCs) is critically important for immune responses to many different pathogens. However, in autoimmune diseases where B cell tolerance is broken, many ASCs secrete autoantibodies and contribute in a major way to organ pathology. The differentiation of B cells into ASCs is controlled by a cohort of key transcription factors including Ets-1, which serves as a negative regulator of this process. In the absence of Ets-1, B cells undergo enhanced differentiation into ASCs many of which secrete autoantibodies as demonstrated by high titers of IgM and IgG autoantibodies in the serum. Recently Toll- like receptor (TLR) signaling, particularly via TLR7 and TLR9, has been implicated in the activation of autoreactive B cells to differentiate into ASCs. Interestingly, Ets-1 deficient B cells exhibit enhanced responses to TLR7 and TLR9 ligands in vitro and Ets-1 knockout mice lacking the TLR adaptor protein Myd88 have reduced autoantibody production. Toll-like receptor signaling is a potent inducer of the expression of Blimp-1, a key transcription factor that drives ASC differentiation. Ets-1 physically interacts with Blimp-1 to inhibit the ability of Blimp-1 to bind target DNA sequences. In contrast, a closely related transcription factor Ets-2 is unable to block Blimp-1 binding or to inhibit ASC differentiation. Ets-1 also is thought to regulate the expression of critical target genes controlling ASC formation, but the identity of most of these targets remains unclear. In this application we propose a variety of assays to further define the role of Ets-1 in regulating target gene expression, Blimp-1 activity and ASC differentiation. These studies will be aided by comparing biological activities of Ets-1, which can block ASC differentiation, with the closely related Ets-2 protein, which lacks this activity. The specific aims of the proposal are (1) to determine which cell types require Ets-1 activity to limit ASC formation, autoantibody secretion and autoimmune disease, (2) to examine the in vivo role of TLR7 and 9 ligands in activating Ets-1 deficient B cells, (3) to identify Ets-1 dependent gene expression pathways regulating ASC formation and (4) to identify structural features of Ets-1 that impart a unique ability to regulate ASC development. Together our studies will provide novel insights into the transcriptional regulation of B cell differentiation particularly in situations of autoantibody secretion.
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DOI:
10.4049/jimmunol.1500165
发表时间:
2015-09-01
期刊:
Journal of immunology (Baltimore, Md. : 1950)
影响因子:
--
作者:
[Mayeux J, Skaug B, Luo W, Russell LM, John S, Saelee P, Abbasi H, Li QZ, Garrett-Sinha LA, Satterthwaite AB]
通讯作者:
Satterthwaite AB
DOI:
10.3389/fimmu.2017.00383
发表时间:
2017
期刊:
Frontiers in immunology
影响因子:
7.3
作者:
[Saelee P, Kearly A, Nutt SL, Garrett-Sinha LA]
通讯作者:
Garrett-Sinha LA
DOI:
10.1016/j.jtauto.2020.100078
发表时间:
2021
期刊:
Journal of translational autoimmunity
影响因子:
3.9
作者:
[Battaglia M, Garrett-Sinha LA]
通讯作者:
Garrett-Sinha LA
DOI:
10.1007/s00018-012-1243-7
发表时间:
2013-09
期刊:
CELLULAR AND MOLECULAR LIFE SCIENCES
影响因子:
8
作者:
[Garrett-Sinha, Lee Ann]
通讯作者:
Garrett-Sinha, Lee Ann
Exploring Roles for Transcription Factor Ets1 in Sjogren's Syndrome
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批准号:10644080
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项目类别:
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资助金额:$17.31万
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财政年份:2023
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依托单位:
Regulation and Consequences of Ets1 Downregulation in B Cells
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批准号:9896768
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项目类别:
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资助金额:$52.41万
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财政年份:2016
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依托单位:
Identification of Specific Roles for Ets-1 in B Cell Tolerance
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批准号:8259852
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项目类别:
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资助金额:$40.96万
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财政年份:2010
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负责人:LEE ANN Garrett-Sinha
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Identification of Specific Roles for Ets-1 in B Cell Tolerance
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批准号:8461248
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项目类别:
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资助金额:$38.85万
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负责人:LEE ANN Garrett-Sinha
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Identification of Specific Roles for Ets-1 in B Cell Tolerance
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批准号:8070010
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项目类别:
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资助金额:$39.98万
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依托单位:
Identification of Specific Roles for Ets-1 in B Cell Tolerance
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批准号:8516184
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资助金额:$4.08万
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Identification of Specific Roles for Ets-1 in B Cell Tolerance
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批准号:7984141
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资助金额:$41.68万
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负责人:LEE ANN Garrett-Sinha
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Identification of Specific Roles for Ets-1 in B Cell Tolerance
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批准号:8264121
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项目类别:
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资助金额:$4.8万
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财政年份:2010
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负责人:LEE ANN Garrett-Sinha
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依托单位:
Ets-1 Expression in Squamous Cells of the Oral Cavity
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批准号:7257725
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项目类别:
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资助金额:$3.96万
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财政年份:2007
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负责人:LEE ANN Garrett-Sinha
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依托单位:
Ets-1 Expression in Squamous Cells of the Oral Cavity
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批准号:7413995
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项目类别:
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资助金额:$3.92万
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财政年份:2007
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负责人:LEE ANN Garrett-Sinha
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依托单位:
FUNCTION OF THE PROTEINS PU1 AND SPI-B IN B LYMPHOCYTES
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批准号:6388750
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项目类别:
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资助金额:$4.38万
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财政年份:2001
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负责人:LEE ANN Garrett-Sinha
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依托单位:
FUNCTION OF THE PROTEINS PU1 AND SPI-B IN B LYMPHOCYTES
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批准号:6182832
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项目类别:
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资助金额:$3.92万
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财政年份:2000
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负责人:LEE ANN Garrett-Sinha
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依托单位:
FUNCTION OF THE PROTEINS PU1 AND SPI-B IN B LYMPHOCYTES
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批准号:2863346
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项目类别:
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资助金额:$3.67万
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财政年份:1999
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负责人:LEE ANN Garrett-Sinha
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依托单位:
海外基金