Project 1: Functional consequences of STAT3 GOF on immune cell signaling
Project 1: Functional consequences of STAT3 GOF on immune cell signaling
批准号:
10576382
负责人:
MEGAN Anne COOPER
金额:
$40.37万
依托单位国家:
美国
项目类别:
财政年份:
2022
资助国家:
美国
项目状态:
未结题
起止时间:
2022-02-17 至 2027-01-31
关键词:
AffectAnimalsAntibodiesAutoantibodiesAutoimmuneAutoimmunityB-LymphocytesBinding SitesCD4 Positive T LymphocytesCTLA4 geneCeliac DiseaseCell physiologyCellsChIP-seqChildChildhoodCodeCollaborationsCytometryDataDefectDiseaseDisease modelFOXP3 geneGene Expression ProfileGenesGeneticGenetic TranscriptionGoalsHeterozygoteHumanHuman GeneticsIL17 geneImiquimodImmuneImmune System DiseasesImmune ToleranceImmune responseImmunologic Deficiency SyndromesImmunological ModelsImmunologicsImpairmentInflammationInstitutionJanus kinaseLaboratoriesMalignant NeoplasmsMature B-LymphocyteMendelian disorderModelingMolecularMusNeutrophil InfiltrationPathway interactionsPatientsPeripheralPeripheral Blood Mononuclear CellPhage DisplayPhage ImmunoPrecipitation SequencingPharmaceutical PreparationsPhenotypePopulationPrecision therapeuticsPredispositionProductionProteomePsoriasisRegulatory T-LymphocyteRiskSTAT3 geneSamplingSignal TransductionSkinSyndromeSystemT cell responseT-LymphocyteTechniquesThymus GlandVariantWorkadaptive immune responsecancer riskcell typecytopeniaearly onsetexome sequencinggain of functionhigh dimensionalityinterestinterleukin-22kinase inhibitorloss of functionmouse modelnovelorgan growthperipheral bloodpersonalized medicineresponsesingle-cell RNA sequencingsynergismtargeted treatmenttreatment comparison
中文摘要
项目摘要/摘要
原发免疫失调综合征是一组影响免疫耐受的罕见单基因疾病
并导致早发性免疫缺陷、自身免疫和恶性风险。STAT3函数增益
(GoF)综合征最近被描述为一种导致早发的原发免疫失调综合征
多重自身免疫和淋巴组织增殖。虽然我们对STAT3的遗传基础有了很好的了解
GOF综合征,免疫失调的潜在机制和相关细胞类型
对于疾病的靶向治疗还不太清楚。我们假设STAT3GOF导联的T细胞调节失调
这是一种相关的细胞类型,可以作为治疗的靶点。我们将调查这一假设
与安德森和马森博士合作,通过深入询问患者的免疫反应
STAT3GOF和使用新的小鼠疾病模型。该项目的长期目标是了解如何
STAT3 GOF失去免疫耐受以更好地了解免疫耐受的机制
并为这种和其他罕见的免疫性疾病的治疗提供个性化和精确的治疗
儿童时期的疾病。在这个项目中,我们将通过以下几个方面研究免疫失调的机制:1)识别
STAT3中改变功能和询问由STAT3 GOF改变的免疫细胞信号的变体
使用原始患者样本和来自STAT3 GOF小鼠模型的细胞进行测序;2)
使用广泛的方法从患者样本中识别新的自身抗体;以及3)调查
STAT3GOF小鼠皮肤炎症模型以确定疾病模型和
询问对JAK抑制的反应。
英文摘要
Project Summary/Abstract
Primary immune dysregulation syndromes are group of rare monogenic disorders affecting immune tolerance
and leading to early-onset immunodeficiency, autoimmunity, and risk of malignancy. STAT3 gain-of-function
(GOF) syndrome was recently described as a primary immune dysregulation syndrome causing early-onset
polyautoimmunity and lymphoproliferation. While we have a good understanding of the genetic basis of STAT3
GOF syndrome, the underlying mechanisms of immune dysregulation and relevant cell types that should be
targeted for therapy of disease are less clear. We hypothesize that dysregulation of T cells in STAT3 GOF leads
to disease and that this is a relevant cell type that can be targeted for therapy. We will investigate this hypothesis
in collaboration with Drs. Anderson and Marson by deeply interrogating the immune response in patients with
STAT3 GOF and using new mouse models of disease. The long-term goals of this project are to understand how
immune tolerance is lost with STAT3 GOF to gain a better understanding of mechanisms of immune tolerance
in humans and provide personalized and precision therapy for the treatment of this and other rare immunologic
diseases of childhood. In this project we will investigate mechanisms of immune dysregulation by: 1) identifying
the variants in STAT3 that alter function and interrogating immune cells signals that are altered by STAT3 GOF
using primary patient samples and cells from murine models of STAT3 GOF using sequencing techniques; 2)
Identifying novel autoantibodies from patient samples using a broad-based approach; and 3) Investigating a
model of skin inflammation in STAT3 GOF mice to determine relevant cell types in a disease model and
interrogate the response to JAK inhibition.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Genetic Mosaicism in Inborn Errors of Immunity
-
批准号:10432960
-
项目类别:
-
资助金额:$19.69万
-
财政年份:2022
-
负责人:MEGAN Anne COOPER
-
依托单位:
Genetic Mosaicism in Inborn Errors of Immunity
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批准号:10560596
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项目类别:
-
资助金额:$23.63万
-
财政年份:2022
-
负责人:MEGAN Anne COOPER
-
依托单位:
Project 1: Functional consequences of STAT3 GOF on immune cell signaling
-
批准号:10328101
-
项目类别:
-
资助金额:$39.38万
-
财政年份:2022
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负责人:MEGAN Anne COOPER
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依托单位:
Genome Engineering Core
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批准号:10704276
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项目类别:
-
资助金额:$22.9万
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财政年份:2018
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负责人:MEGAN Anne COOPER
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依托单位:
METABOLIC REGULATION OF NATURAL KILLER CELL ACTIVATION
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批准号:9914085
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项目类别:
-
资助金额:$38.13万
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财政年份:2017
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负责人:MEGAN Anne COOPER
-
依托单位:
METABOLIC REGULATION OF NATURAL KILLER CELL ACTIVATION
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批准号:9383758
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项目类别:
-
资助金额:$38.13万
-
财政年份:2017
-
负责人:MEGAN Anne COOPER
-
依托单位:
Metabolic Regulation of Natural Killer Cell Activation
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批准号:10789052
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项目类别:
-
资助金额:$30.0万
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财政年份:2017
-
负责人:MEGAN Anne COOPER
-
依托单位:
Mechanisms of Innate Immune Memory
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批准号:8433313
-
项目类别:
-
资助金额:$12.01万
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财政年份:2010
-
负责人:MEGAN Anne COOPER
-
依托单位:
Mechanisms of Innate Immune Memory
-
批准号:8215687
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项目类别:
-
资助金额:$12.01万
-
财政年份:2010
-
负责人:MEGAN Anne COOPER
-
依托单位:
Mechanisms of Innate Immune Memory
-
批准号:8616021
-
项目类别:
-
资助金额:$12.01万
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财政年份:2010
-
负责人:MEGAN Anne COOPER
-
依托单位:
Mechanisms of Innate Immune Memory
-
批准号:7770417
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项目类别:
-
资助金额:$12.01万
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财政年份:2010
-
负责人:MEGAN Anne COOPER
-
依托单位:
Mechanisms of Innate Immune Memory
-
批准号:8035927
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项目类别:
-
资助金额:$12.01万
-
财政年份:2010
-
负责人:MEGAN Anne COOPER
-
依托单位:
The Role of STAT3 in Pediatric Autoimmunity
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批准号:8912037
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项目类别:
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资助金额:$9.29万
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财政年份:--
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负责人:MEGAN Anne COOPER
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依托单位:
The Role of STAT3 in Pediatric Autoimmunity
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批准号:8712821
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项目类别:
-
资助金额:$7.94万
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财政年份:--
-
负责人:MEGAN Anne COOPER
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依托单位:
海外基金