Targeting Tfh Cell Metabolic Regulation in SLE and SLE-Associated Atherosclerosis
针对 SLE 和 SLE 相关动脉粥样硬化的 Tfh 细胞代谢调节
基本信息
- 批准号:10609478
- 负责人:
- 金额:$ 55.69万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2020
- 资助国家:美国
- 起止时间:2020-05-20 至 2025-04-30
- 项目状态:未结题
- 来源:
- 关键词:ATP Citrate (pro-S)-LyaseAccelerationAcetyl Coenzyme AAcetylationAddressAffectAffinityAnabolismAnimal ModelAntigen-Antibody ComplexArthritisAtherosclerosisAutoantibodiesAutoimmune DiseasesAutoimmunityB-LymphocytesBioenergeticsBone MarrowCD4 Positive T LymphocytesCardiovascular DiseasesCause of DeathCellsCellular Metabolic ProcessCharacteristicsChimera organismChromatinChronicCitratesClinical TrialsConsumptionCoronary ArteriosclerosisDNADataDefectDepositionDiseaseEpigenetic ProcessEventFrequenciesGene ExpressionGeneticGlucoseGlucose TransporterGlutaminaseGlutamineHelper-Inducer T-LymphocyteHistone AcetylationHistonesImmuneImmunosuppressionImpairmentIndividualInflammationInflammatoryInvestigationKnock-outMediatingMedicalMetabolicMetabolic PathwayMetabolismMethylationModelingModificationMusNephritisPathway interactionsPatientsPhase II Clinical TrialsPlayProductionProliferatingPublishingRegulationRegulatory T-LymphocyteRoleSLEB1 geneSignal TransductionStructure of germinal center of lymph nodeSystemic Lupus ErythematosusT cell differentiationT-Cell ActivationT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticWorkalpha ketoglutarateanti-cancerautoreactive B cellchronic graft versus host diseasecomorbidityconditional knockoutcytokinedrug repurposingeffective therapyepigenetic regulationglucose uptakehistone methylationin vivo Modelinhibitorinsightmortalitymouse modelnew therapeutic targetnovelpathogenic autoantibodiesprogramsresponseside effecttherapeutic targettransgene expressiontumor metabolismvascular inflammation
项目摘要
PROJECT SUMMARY
Systemic lupus erythematosus (SLE) is characterized by autoantibody production and immune complex
deposition and affects five to seven million individuals worldwide. Atherosclerosis and cardiovascular disease
are common causes of early mortality in SLE, but immune-mediated mechanisms leading to this and other
disease sequelae are not well understood. Therefore, demand is high to identify targeted strategies to
overcome the undesirable side-effects of overt immunosuppression. In this application, we propose that the
cellular metabolism of follicular helper T cells (Tfh), critical in promoting autoreactive B cell responses, may
provide novel SLE therapeutic targets. Conversely, regulatory T cells (Treg) may protect. Our group has
demonstrated that activated T cells increase glucose and glutamine consumption as they proliferate and
differentiate into specific functional subsets. Importantly, differentiation and biosynthesis following activation
requires a distinct metabolic program. To date, Tfh metabolism remains poorly understood, but our data
suggest that both glucose and glutamine are essential and that Tfh appear to have high rates of glutaminolysis
and are limited by rates of glucose uptake. It is now clear that these metabolic pathways regulate chromatin
accessibility and gene expression by providing substrates for epigenetic modifications. Our data suggest that
Glutaminase (GLS) and ATP-Citrate Lyase (ACLY), which regulate glutamine-dependent production of α-
ketoglutarate (αKG) and conversion of glucose-derived citrate to acetyl-CoA, respectively, regulate epigenetic
marks, gene expression and differentiation essential for Tfh function. These observations build on our previous
work demonstrating that GLS-inhibition led to reduced αKG and differential alterations to histone methylation
and chromatin accessibility in CD4 Th1 and Th17 cells. Importantly, both GLS and ACLY-deficient T cells failed
to generate or maintain Tfh in an in vivo model of chronic inflammation. We have also used a model for SLE-
accelerated atherosclerosis and shown that T cells in atherosclerosis have increased rates of
metabolism. Further, Treg had reduced function and Tfh frequencies were increased. The current proposal
will test the hypothesis that Tfh cells require glutamine and citrate metabolism to regulate epigenetic marks and
chromatin accessibility to allow gene expression for germinal centers and autoantibody production in SLE and
that targeting GLS or ACLY will disrupt epigenetic regulation of Tfh differentiation to treat disease. We will: (1)
Establish the role of GLS and ACLY in differentiation, epigenetic regulation and gene expression, and
metabolism of Tfh cells, and (2) Test inhibition of GLS or ACLY to decrease autoantibody production in murine
SLE and impair circulating Tfh from SLE patients, and (3) determine the effect of manipulating Tfh metabolism
on SLE-accelerated atherosclerosis. Our proposal to test the metabolic regulators of epigenetic marks and Tfh
differentiation will leverage two targets that are currently under investigation as anti-cancer metabolism
therapeutics and will determine if repurposing these drugs may offer new opportunities in SLE.
项目摘要
系统性红斑狼疮(SLE)以自身抗体产生和免疫复合物为特征
它影响着全世界500万到700万人。动脉粥样硬化和心血管疾病
是SLE早期死亡的常见原因,但导致这种和其他疾病的免疫介导机制
疾病的后遗症还不太清楚。因此,确定有针对性的战略的需求很高,
克服明显的免疫抑制的不良副作用。在本申请中,我们提出,
在促进自身反应性B细胞应答中起关键作用的滤泡辅助性T细胞(Tfh)的细胞代谢可能
提供新的SLE治疗靶点。相反,调节性T细胞(Treg)可以保护。我们集团
表明活化的T细胞在增殖时增加葡萄糖和谷氨酰胺的消耗,
分化为特定的功能子集。重要的是,活化后的分化和生物合成
需要一个独特的代谢程序到目前为止,转铁蛋白代谢仍然知之甚少,但我们的数据
表明葡萄糖和谷氨酰胺都是必需,Tfh似乎具有较高的β-氨基水解率
并且受到葡萄糖摄取速率的限制。现在很清楚,这些代谢途径调节染色质
通过为表观遗传修饰提供底物,可及性和基因表达。我们的数据表明
谷氨酰胺酶(GLS)和ATP-柠檬酸裂解酶(ACLY),调节谷氨酰胺依赖的α-
酮戊二酸(αKG)和葡萄糖衍生的柠檬酸盐转化为乙酰辅酶A,分别调节表观遗传
标志物、基因表达和Tfh功能所必需的分化。这些观察建立在我们以前的基础上。
研究表明,GLS抑制导致αKG降低和组蛋白甲基化的差异改变
和CD 4 Th 1和Th 17细胞中的染色质可及性。重要的是,GLS和ACLY缺陷的T细胞都失败了。
以在慢性炎症的体内模型中产生或维持Tfh。我们还使用了SLE的模型-
加速动脉粥样硬化,并显示动脉粥样硬化中的T细胞具有增加的
新陈代谢.此外,Treg功能降低,Tfh频率增加。现时的建议
将检验Tfh细胞需要谷氨酰胺和柠檬酸盐代谢来调节表观遗传标记的假设,
染色质可及性允许SLE中生发中心和自身抗体产生的基因表达,
靶向GLS或ACLY将破坏Tfh分化的表观遗传调节以治疗疾病。我们将:(1)
确定GLS和ACLY在分化、表观遗传调控和基因表达中的作用,
(2)测试GLS或ACLY的抑制作用以减少小鼠中自身抗体的产生
SLE和SLE患者受损的循环Tfh,以及(3)确定操纵Tfh代谢的效果
SLE加速的动脉粥样硬化我们的建议是测试表观遗传标记和转铁蛋白的代谢调节因子
分化将利用目前正在研究的两个靶点作为抗癌代谢
并将确定重新利用这些药物是否可以为SLE提供新的机会。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
AMY S MAJOR其他文献
AMY S MAJOR的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('AMY S MAJOR', 18)}}的其他基金
Investigating mechanisms of oxidized phospholipid-mediated dysregulation of regulatory T cells in atherosclerosis
研究动脉粥样硬化中氧化磷脂介导的调节性 T 细胞失调的机制
- 批准号:
10648711 - 财政年份:2023
- 资助金额:
$ 55.69万 - 项目类别:
Fc Receptors in Atherosclerosis: Linking Innate and Adaptive Immunity.
Fc§§ 动脉粥样硬化受体:连接先天免疫和适应性免疫。
- 批准号:
10450688 - 财政年份:2021
- 资助金额:
$ 55.69万 - 项目类别:
Fc Receptors in Atherosclerosis: Linking Innate and Adaptive Immunity.
Fc§§ 动脉粥样硬化受体:连接先天免疫和适应性免疫。
- 批准号:
10664909 - 财政年份:2021
- 资助金额:
$ 55.69万 - 项目类别:
Fc Receptors in Atherosclerosis: Linking Innate and Adaptive Immunity.
Fc§§ 动脉粥样硬化受体:连接先天免疫和适应性免疫。
- 批准号:
10259917 - 财政年份:2021
- 资助金额:
$ 55.69万 - 项目类别:
Targeting Tfh Cell Metabolic Regulation in SLE and SLE-Associated Atherosclerosis
针对 SLE 和 SLE 相关动脉粥样硬化的 Tfh 细胞代谢调节
- 批准号:
10029497 - 财政年份:2020
- 资助金额:
$ 55.69万 - 项目类别:
Targeting Tfh Cell Metabolic Regulation in SLE and SLE-Associated Atherosclerosis
针对 SLE 和 SLE 相关动脉粥样硬化的 Tfh 细胞代谢调节
- 批准号:
10380090 - 财政年份:2020
- 资助金额:
$ 55.69万 - 项目类别:
Immunological Mechanisms of Disease Training Program
疾病免疫机制培训计划
- 批准号:
10640277 - 财政年份:2019
- 资助金额:
$ 55.69万 - 项目类别:
Immunological Mechanisms of Disease Training Program
疾病免疫机制培训计划
- 批准号:
9791561 - 财政年份:2019
- 资助金额:
$ 55.69万 - 项目类别:
Immunological Mechanisms of Disease Training Program
疾病免疫机制培训计划
- 批准号:
10413896 - 财政年份:2019
- 资助金额:
$ 55.69万 - 项目类别:
Targeting the T cell immune synapse in autoimmunity
自身免疫中靶向 T 细胞免疫突触
- 批准号:
9406059 - 财政年份:2017
- 资助金额:
$ 55.69万 - 项目类别:
相似海外基金
SHINE: Origin and Evolution of Compressible Fluctuations in the Solar Wind and Their Role in Solar Wind Heating and Acceleration
SHINE:太阳风可压缩脉动的起源和演化及其在太阳风加热和加速中的作用
- 批准号:
2400967 - 财政年份:2024
- 资助金额:
$ 55.69万 - 项目类别:
Standard Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328975 - 财政年份:2024
- 资助金额:
$ 55.69万 - 项目类别:
Continuing Grant
EXCESS: The role of excess topography and peak ground acceleration on earthquake-preconditioning of landslides
过量:过量地形和峰值地面加速度对滑坡地震预处理的作用
- 批准号:
NE/Y000080/1 - 财政年份:2024
- 资助金额:
$ 55.69万 - 项目类别:
Research Grant
Market Entry Acceleration of the Murb Wind Turbine into Remote Telecoms Power
默布风力涡轮机加速进入远程电信电力市场
- 批准号:
10112700 - 财政年份:2024
- 资助金额:
$ 55.69万 - 项目类别:
Collaborative R&D
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328973 - 财政年份:2024
- 资助金额:
$ 55.69万 - 项目类别:
Continuing Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328972 - 财政年份:2024
- 资助金额:
$ 55.69万 - 项目类别:
Continuing Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
- 批准号:
2332916 - 财政年份:2024
- 资助金额:
$ 55.69万 - 项目类别:
Standard Grant
Collaborative Research: A new understanding of droplet breakup: hydrodynamic instability under complex acceleration
合作研究:对液滴破碎的新认识:复杂加速下的流体动力学不稳定性
- 批准号:
2332917 - 财政年份:2024
- 资助金额:
$ 55.69万 - 项目类别:
Standard Grant
Collaborative Research: FuSe: R3AP: Retunable, Reconfigurable, Racetrack-Memory Acceleration Platform
合作研究:FuSe:R3AP:可重调、可重新配置、赛道内存加速平台
- 批准号:
2328974 - 财政年份:2024
- 资助金额:
$ 55.69万 - 项目类别:
Continuing Grant
Radiation GRMHD with Non-Thermal Particle Acceleration: Next-Generation Models of Black Hole Accretion Flows and Jets
具有非热粒子加速的辐射 GRMHD:黑洞吸积流和喷流的下一代模型
- 批准号:
2307983 - 财政年份:2023
- 资助金额:
$ 55.69万 - 项目类别:
Standard Grant