Signaling and Transcriptional Control of T Follicular Helper Cells and RBC Alloimmunization
滤泡辅助 T 细胞和红细胞同种免疫的信号传导和转录控制
基本信息
- 批准号:9753378
- 负责人:
- 金额:$ 20.19万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-01 至 2020-08-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAlloimmunizationAntibodiesAntibody ResponseAntigensAutoimmune DiseasesAutomobile DrivingBlood TransfusionCD4 Positive T LymphocytesCell Differentiation processCell physiologyCellsChronicClinicalComplicationDevelopmentDiagnosticErythrocytesEventExposure toFamilyGenerationsGenesGeneticGoalsHelper-Inducer T-LymphocyteHumanImmuneImmune responseImmune systemImmunizeIn VitroIncidenceInflammatoryInterferon Type IIIsoantibodiesLifeLymphocyteMYB geneMaintenanceMembrane ProteinsMemoryMolecularMolecular TargetMusMutagenesisPathway interactionsPatient CarePatientsPersonsPlayPregnancyProductionProtocols documentationPublic HealthPublishingReactionRegulationResourcesRoleSavingsSickle Cell AnemiaSignal TransductionStimulusStructure of germinal center of lymph nodeSystemSystemic Lupus ErythematosusT memory cellT-LymphocyteTNF geneTestingTherapeuticThinkingTimeTranscriptional RegulationTransfusionbasecell typecellular targetingcytokinedruggable targetfactor Chigh riskimprovedin vivointerestlupus prone micemouse modelpatient populationreceptorresponsetranscription factortransfusion medicine
项目摘要
PROJECT ABSTRACT
RBC alloimmunization represents a major complication of chronic transfusion therapy. For those patients who
are unfortunate enough to generate multiple alloantibodies, provision of compatible antigen negative RBCs can
be both time and resource intensive. Despite the clinical importance of alloantibodies, the molecular regulators
of alloantibody production remain largely unknown. Patients with autoimmune diseases such as Systemic Lupus
Erythematosus (SLE) have both higher rates of alloimmunization and aberrant T follicular helper cell (TFH)
differentiation. Given the central role that TFH play in the generation of antibody responses, we are focused on
understanding how SLE-associated pathways and downstream signaling events control TFH differentiation and
alloimmunization responses in mice and humans. This proposal builds on the complementary expertise and
recent findings from three different labs regarding the molecular control of TFH differentiation and function: (i)
the Luckey lab and expertise with TFH differentiation in mouse models of alloimmunization, (ii) the Erickson lab
with expertise with TFH differentiation in SLE mouse models and their regulation by the TNF family cytokine
BAFF, and (iii) the Bender lab with expertise in TFH differentiation regulation by the transcription factor c-Myb.
Our overarching hypothesis is that mice expressing SLE-associated genes will drive increased alloantibody
generation in response to transfusion, and that BAFF signaling in T cells is a central driver of TFH differentiation
and function in this setting. We subsequently hypothesize that BAFF signaling drives c-Myb expression, which
in turn influences the accumulation of TFH and drives memory TFH formation. Finally, we hypothesize that both
BAFF and c-Myb similarly control human TFH differentiation. By better understanding the molecular regulators
of TFH differentiation and alloimmunization, we anticipate that in the fullness of time the results of these proposed
studies will lead to the development of both clinically useful diagnostics and therapeutically druggable targets,
ultimately helping to improve the lives of those chronically transfused patients who suffer most from the
consequences of RBC alloimmunization.
项目摘要
红细胞同种异体免疫是慢性输血治疗的主要并发症。对于那些
不幸的是产生多种同种异体抗体,提供相容的抗原阴性的红细胞可以
既要耗费时间,又要耗费资源。尽管同种异体抗体具有临床重要性,但分子调节器
同种异体抗体的产生在很大程度上仍不清楚。系统性红斑狼疮等自身免疫性疾病患者
红斑狼疮(SLE)具有较高的同种异体免疫率和异常T滤泡辅助细胞(TFH)
差异化。鉴于TFH在产生抗体反应中所起的中心作用,我们将重点放在
了解SLE相关通路和下游信号事件如何控制TFH分化和
小鼠和人类的同种异体免疫反应。这项建议建立在互补的专业知识和
三个不同实验室关于TFH分化和功能的分子控制的最新发现:(I)
Luckey实验室和同种异体免疫小鼠模型中TFH分化的专业知识,(Ii)Erickson实验室
在系统性红斑狼疮小鼠模型中TFH的分化以及肿瘤坏死因子家族对其调节方面的专业知识
Baff,以及(Iii)Bender实验室,拥有转录因子c-Myb调控TFH分化的专业知识。
我们的主要假设是,表达SLE相关基因的小鼠将驱动增加的同种异体抗体
T细胞中的BAFF信号是TFH分化的中心驱动因素
并在这种环境下发挥作用。我们随后假设BAFF信号驱动c-Myb的表达,这
反过来,影响TFH的积累,并驱动记忆TFH的形成。最后,我们假设两者
Baff和c-Myb类似地控制人类TFH的分化。通过更好地了解分子调节器
关于TFH分化和同种异体免疫,我们预计在充分的时间里,这些建议的结果
研究将导致临床上有用的诊断和治疗上可用药物靶点的发展,
最终帮助改善那些长期输血的患者的生活,这些患者遭受的
红细胞异体免疫的后果。
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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Timothy P. Bender其他文献
Differentiation of mouse erythroleukemia cells is blocked by late up-regulation of a c-myb transgene
c-myb 转基因的晚期上调阻碍了小鼠红白血病细胞的分化
- DOI:
10.1128/mcb.10.2.705-710.1990 - 发表时间:
1990 - 期刊:
- 影响因子:5.3
- 作者:
Diana McCLINTON;Jeannine Stafford;Leslie;Brents;Timothy P. Bender;W. Michael;'. Kuehl - 通讯作者:
'. Kuehl
Expression of a transfected human c-myconcogene inhibits differentiation of a mouse erythroleukaemia cell line
转染的人 c-myc 癌基因的表达抑制小鼠红白血病细胞系的分化
- DOI:
10.1038/322748a0 - 发表时间:
1986-08-21 - 期刊:
- 影响因子:48.500
- 作者:
Ethan Dmitrovsky;W. Michael Kuehl;Gregory F. Hollis;Ilan R. Kirsch;Timothy P. Bender;Shoshana Segal - 通讯作者:
Shoshana Segal
Considerations for the physical vapor deposition of high molar mass organic compounds
- DOI:
10.1016/j.vacuum.2014.05.023 - 发表时间:
2014-11-01 - 期刊:
- 影响因子:
- 作者:
Jeffrey S. Castrucci;Jeremy D. Dang;Brett A. Kamino;Andrew Campbell;David Pitts;Zheng-Hong Lu;Timothy P. Bender - 通讯作者:
Timothy P. Bender
Redox behaviour of boron subphthalocyanine carbon nanotube composites
- DOI:
10.1016/j.nxmate.2024.100163 - 发表时间:
2024-04-01 - 期刊:
- 影响因子:
- 作者:
Raunaq Bagchi;Erika Remigio;Dian Yu;Nina F. Farac;Averey Kudlow;Jane Howe;Timothy P. Bender;Keryn Lian - 通讯作者:
Keryn Lian
Timothy P. Bender的其他文献
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{{ truncateString('Timothy P. Bender', 18)}}的其他基金
c-Myb in CD4 T cells is crucial for recall antibody responses
CD4 T 细胞中的 c-Myb 对于记忆抗体反应至关重要
- 批准号:
8820986 - 财政年份:2014
- 资助金额:
$ 20.19万 - 项目类别:
c-Myb controls survival, proliferation and differentiation during B-lymphopoiesis
c-Myb 控制 B 淋巴细胞生成过程中的存活、增殖和分化
- 批准号:
8478146 - 财政年份:2011
- 资助金额:
$ 20.19万 - 项目类别:
c-Myb fusion proteins in Adenoid Cystic Carcinoma
腺样囊性癌中的 c-Myb 融合蛋白
- 批准号:
8303226 - 财政年份:2011
- 资助金额:
$ 20.19万 - 项目类别:
c-Myb controls survival, proliferation and differentiation during B-lymphopoiesis
c-Myb 控制 B 淋巴细胞生成过程中的存活、增殖和分化
- 批准号:
8665994 - 财政年份:2011
- 资助金额:
$ 20.19万 - 项目类别:
c-Myb controls survival, proliferation and differentiation during B-lymphopoiesis
c-Myb 控制 B 淋巴细胞生成过程中的存活、增殖和分化
- 批准号:
8162936 - 财政年份:2011
- 资助金额:
$ 20.19万 - 项目类别:
c-Myb controls survival, proliferation and differentiation during B-lymphopoiesis
c-Myb 控制 B 淋巴细胞生成过程中的存活、增殖和分化
- 批准号:
8325520 - 财政年份:2011
- 资助金额:
$ 20.19万 - 项目类别:
c-Myb fusion proteins in Adenoid Cystic Carcinoma
腺样囊性癌中的 c-Myb 融合蛋白
- 批准号:
8174241 - 财政年份:2011
- 资助金额:
$ 20.19万 - 项目类别:
相似海外基金
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