Alteration of function and specificity of TFH in SLE
SLE 中 TFH 功能和特异性的改变
基本信息
- 批准号:10650347
- 负责人:
- 金额:$ 55.16万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-07-05 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAgreementAnti-DNA AntibodiesAntigen PresentationAntigen Presentation PathwayAutoantibodiesAutoimmuneAutoimmune DiseasesAutoimmunityB-Cell ActivationB-LymphocytesCD4 Positive T LymphocytesCell Differentiation processCell SeparationCell physiologyCellsChronicClinical TrialsCoculture TechniquesComplexDataDendritic CellsDevelopmentDiseaseDisease ProgressionDisease modelEstradiolEstrogen ReceptorsEstrogensFailureFemaleFrequenciesGenderGene ExpressionGene Expression ProfileGenesGenetic Predisposition to DiseaseGlomerulonephritisGonadal Steroid HormonesHelper-Inducer T-LymphocyteHeterogeneityHormonalITGAX geneImmuneImmune System DiseasesIn VitroIndividualKnowledgeLoxP-flanked alleleModelingMusMutationPRDM1 genePathogenesisPathogenicityPathologyPatientsPatternPeripheralPersonsPhenocopyPlayReceptor SignalingRegulationReporterRisk FactorsRoleSelective Estrogen Receptor ModulatorsSex ChromosomesSignal TransductionSpecificitySpleenStructure of germinal center of lymph nodeSystemic Lupus ErythematosusT cell regulationT-LymphocyteT-cell receptor repertoireTestingTherapeuticThymus Glandantigen processingautoreactive B cellautoreactive T cellautoreactivityconditional knockoutdisease phenotypeeffector T cellgenetic risk factorgenome wide association studyhormone regulationin vivoinsightlupus prone micelupus-likemouse modelnanoparticlenovel therapeuticspatient subsetsprecision medicinereceptor-mediated signalingresponserisk variantsystemic autoimmune diseasethymocyteyoung woman
项目摘要
Project Summary/ Abstract
Systemic lupus erythematosus (SLE) is a chronic and complex autoimmune disease and
pathogenic mechanisms are not well understood. Based on data from SLE patients and GWAS,
we developed a mouse model to phenocopy the expression pattern of the PRDM1 risk allele.
Mice with a selective deficiency of BLIMP1 in dendritic cells (DCs) (Prdm1 CKO mice) develop
SLE with an increased number of T follicular helper cells (TFH) and autoantibodies arising in a
germinal center response. Only female mice develop disease. The central hypothesis for the
proposed studies is that BLIMP1-deficient DCs alter the selection of T cells in the thymus. We
further hypothesize that estrogen and estrogen-receptor mediated signaling play a critical role in
BLIMP1-deficient DC function, altering antigen presentation and synergizing with BLIMP1
deficiency to skew to TFH differentiation. The following aims will address these hypotheses. Aim
1 will determine if the altered TFH repertoire in female Prdm1 CKO mice is determined during
thymic selection. We will identify whether BLIMP1-deficient DCs alter the strength of TCR
signaling to alter the T cell repertoire. We will explore the function of TFH in female Prdm1 CKO
mice and female control mice, and their activation of autoreactive B cells. Aim 2 will
investigate functional changes in DCs and TFH conferred by estrogen receptor signaling. These
studies should suggest therapeutic strategies in a defined subset of SLE patients, and
advance precision medicine in a disease where many agree that the failure of clinical
trials reflects an inadequate understanding of patient heterogeneity.
项目概要/摘要
系统性红斑狼疮(SLE)是一种慢性、复杂的自身免疫性疾病,
致病机制尚不清楚。根据 SLE 患者和 GWAS 的数据,
我们开发了一个小鼠模型来对 PRDM1 风险等位基因的表达模式进行表型复制。
树突状细胞 (DC) 中选择性缺乏 BLIMP1 的小鼠(Prdm1 CKO 小鼠)发育
系统性红斑狼疮 (SLE) 中滤泡辅助性 T 细胞 (TFH) 和自身抗体数量增加
生发中心反应。只有雌性小鼠才会患病。中心假设为
拟议的研究表明,BLIMP1 缺陷的 DC 会改变胸腺中 T 细胞的选择。我们
进一步假设雌激素和雌激素受体介导的信号在
BLIMP1 缺陷的 DC 功能,改变抗原呈递并与 BLIMP1 协同作用
缺乏会导致 TFH 分化。以下目标将解决这些假设。目的
1 将确定雌性 Prdm1 CKO 小鼠中改变的 TFH 库是否在
胸腺选择。我们将确定 BLIMP1 缺陷的 DC 是否会改变 TCR 的强度
改变 T 细胞库的信号。我们将探讨 TFH 在女性 Prdm1 CKO 中的功能
小鼠和雌性对照小鼠,以及它们自身反应性 B 细胞的激活。目标2将
研究雌激素受体信号传导赋予 DC 和 TFH 的功能变化。这些
研究应针对特定的 SLE 患者提出治疗策略,并且
在这种疾病中推进精准医学,许多人都认为临床治疗的失败
试验反映出对患者异质性的认识不足。
项目成果
期刊论文数量(1)
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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Betty Diamond其他文献
Betty Diamond的其他文献
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{{ truncateString('Betty Diamond', 18)}}的其他基金
Origin and function of atypical lymphocyte populations in inflamed tissue in SLE and RA
SLE 和 RA 炎症组织中非典型淋巴细胞群的起源和功能
- 批准号:
10088788 - 财政年份:2021
- 资助金额:
$ 55.16万 - 项目类别:
Origin and function of atypical lymphocyte populations in inflamed tissue in SLE and RA
SLE 和 RA 炎症组织中非典型淋巴细胞群的起源和功能
- 批准号:
10427145 - 财政年份:2021
- 资助金额:
$ 55.16万 - 项目类别:
Origin and function of atypical lymphocyte populations in inflamed tissue in SLE and RA
SLE 和 RA 炎症组织中非典型淋巴细胞群的起源和功能
- 批准号:
10598097 - 财政年份:2021
- 资助金额:
$ 55.16万 - 项目类别:
Effect of Covid-19 engagement of ACE2 on brain health and pathology
Covid-19 与 ACE2 的结合对大脑健康和病理学的影响
- 批准号:
10151985 - 财政年份:2020
- 资助金额:
$ 55.16万 - 项目类别:
Alteration of function and specificity of TFH in SLE
SLE 中 TFH 功能和特异性的改变
- 批准号:
9973185 - 财政年份:2019
- 资助金额:
$ 55.16万 - 项目类别:
Alteration of function and specificity of TFH in SLE
SLE 中 TFH 功能和特异性的改变
- 批准号:
10196943 - 财政年份:2019
- 资助金额:
$ 55.16万 - 项目类别:
Alteration of function and specificity of TFH in SLE
SLE 中 TFH 功能和特异性的改变
- 批准号:
10437692 - 财政年份:2019
- 资助金额:
$ 55.16万 - 项目类别:
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