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

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)
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会议论文数量(0)
专利数量(0)

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AMY S MAJOR其他文献

AMY S MAJOR的其他文献

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{{ 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:

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