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.
项目总结
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
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
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
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
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
Study of the Particle Acceleration and Transport in PWN through X-ray Spectro-polarimetry and GeV Gamma-ray Observtions
通过 X 射线光谱偏振法和 GeV 伽马射线观测研究 PWN 中的粒子加速和输运
- 批准号:
23H01186 - 财政年份:2023
- 资助金额:
$ 55.69万 - 项目类别:
Grant-in-Aid for Scientific Research (B)














{{item.name}}会员




