Defining the Pathogenic Contribution of High Genotypic MIF Expression

定义高基因型 MIF 表达的致病贡献

基本信息

  • 批准号:
    10094724
  • 负责人:
  • 金额:
    $ 36.85万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-06-01 至 2026-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Rheumatoid arthritis (RA) remains incurable despite biologic therapies. We previously identified a functional promoter polymorphism in the gene for macrophage migration inhibitory factor (MIF) - a cytokine our group first cloned, that is associated with erosive joint destruction in RA. MIF is known to regulate the innate response by inhibiting glucocorticoid action, suppressing activation-induced apoptosis, and promoting macrophage retention in tissues. The role of MIF and high expression MIF alleles is not fully understood however, especially with respect to alterations in the adaptive response that perpetuate inflammation, pathologic progression, and disease persistence. We have discovered a novel T cell subpopulation that expresses the MIF receptor (CD74), expands during arthritis, and recapitulates disease when transferred into naïve hosts. A similar population exists in human rheumatoid synovium. We hypothesize that CD4+CD74+ T cells play a key role in rheumatoid inflammation, disease progression, and relapse. We will pursue three Specific Aims in this proposal: 1. Define the pathogenic role of a novel, MIF receptor expressing T cell sub-population (CD4+CD74+ T cells) in inflammatory arthritis. We hypothesize that CD4+CD74+ T cells express inflammatory cytokines and chemotactic receptors that contribute to synovial joint destruction. We will characterize the MIF signaling and effector responses of mouse and human CD4+CD74+ T cells, identify trafficking factors/receptors, and establish their pathogenic potential. 2. Define the impact of high-genotypic MIF expression on joint immunopathology in a novel humanized MIF mouse model. We hypothesize that MIF expression drives pathologic CD4+CD74+ T cell trafficking and effector responses, and unremitting arthritis. We will test this hypothesis using novel humanized MIF mice that express low-expression and high-expression human MIF alleles. 3. Evaluate the impact of ICBP90 inhibition on MIF expression in humanized MIF mice and in high genotypic MIF expressing human cells. We identified both the transcription factor (ICBP90) that upregulates MIF transcription at its variant promoter microsatellite (-794 CATT5-8), and a drug-like molecule (CMFT) that blocks ICBP90 binding to this promoter site. We hypothesize that ICBP90 inhibition will ameliorate the MIF- dependent expansion and effector response of CD4+CD74+ T cells. We will test this possibility in experimental arthritis and examine ICBP90 inhibition in high-genotypic MIF expressing human cells obtained from peripheral blood and from rheumatoid synovial tissue. The completion of these Aims will provide insight into the pathologic role of a novel, MIF receptor expressing T cell population and the contribution of MIF risk alleles to rheumatoid inflammation. These studies also will accelerate consideration of a precision-based approach for treating RA joint destruction.
项目总结

项目成果

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RICHARD J BUCALA其他文献

RICHARD J BUCALA的其他文献

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{{ truncateString('RICHARD J BUCALA', 18)}}的其他基金

Defining the Pathogenic Contribution of High Genotypic MIF Expression
定义高基因型 MIF 表达的致病贡献
  • 批准号:
    10402761
  • 财政年份:
    2021
  • 资助金额:
    $ 36.85万
  • 项目类别:
Defining the Pathogenic Contribution of High Genotypic MIF Expression
定义高基因型 MIF 表达的致病贡献
  • 批准号:
    10624334
  • 财政年份:
    2021
  • 资助金额:
    $ 36.85万
  • 项目类别:
Aging and Innate Immune Mechanisms in Pulmonary Infection
肺部感染的衰老和先天免疫机制
  • 批准号:
    9300969
  • 财政年份:
    2015
  • 资助金额:
    $ 36.85万
  • 项目类别:
Aging and Innate Immune Mechanisms in Pulmonary Infection
肺部感染的衰老和先天免疫机制
  • 批准号:
    8967869
  • 财政年份:
    2015
  • 资助金额:
    $ 36.85万
  • 项目类别:
Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF
疟原虫 MIF 对适应性免疫的炎症抑制
  • 批准号:
    10386832
  • 财政年份:
    2014
  • 资助金额:
    $ 36.85万
  • 项目类别:
Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF
疟原虫 MIF 对适应性免疫的炎症抑制
  • 批准号:
    8664206
  • 财政年份:
    2014
  • 资助金额:
    $ 36.85万
  • 项目类别:
Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF
疟原虫 MIF 对适应性免疫的炎症抑制
  • 批准号:
    8822823
  • 财政年份:
    2014
  • 资助金额:
    $ 36.85万
  • 项目类别:
Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF
疟原虫 MIF 对适应性免疫的炎症抑制
  • 批准号:
    9815245
  • 财政年份:
    2014
  • 资助金额:
    $ 36.85万
  • 项目类别:
Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF
疟原虫 MIF 对适应性免疫的炎症抑制
  • 批准号:
    10614419
  • 财政年份:
    2014
  • 资助金额:
    $ 36.85万
  • 项目类别:
Inflammatory Suppression of Adaptive Immunity by Plasmodium MIF
疟原虫 MIF 对适应性免疫的炎症抑制
  • 批准号:
    9036321
  • 财政年份:
    2014
  • 资助金额:
    $ 36.85万
  • 项目类别:

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