Understanding A Molecular Cascade That Drives Neutrophil Mediated Pathology In Arthritis

了解驱动中性粒细胞介导的关节炎病理学的分子级联

基本信息

  • 批准号:
    10658202
  • 负责人:
  • 金额:
    $ 49.4万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-02-09 至 2028-01-31
  • 项目状态:
    未结题

项目摘要

UNDERSTANDING A MOLECULAR CASCADE THAT DRIVES NEUTROPHIL MEDIATED PATHOLOGY IN ARTHRITIS Rheumatoid arthritis (RA) is a frequent chronic disease of the synovial joints characterized by painful loss of mobility due to unrestrained inflammation and progressive bone erosion. Disease etiology is poorly characterized, and the available therapeutic approaches fail to control disease symptoms in many RA patients, highlighting the critical need for identification of new therapeutic targets. A key event in RA is the influx of leukocytes, such as neutrophils, into the joints, where they initiate and sustain inflammation and contribute to bone erosion from the early stages of RA. While healthy synovial fluid is acellular, the most abundant cell type found in the inflamed synovial fluid is the activated neutrophil. Engulfment and cell motility protein-1 (ELMO1) is a regulator of actin cytoskeleton dynamics during phagocytosis of dying cells and migration of lymphocytes. We demonstrated that Elmo1–/– mice develop significantly milder disease in two models of inflammatory arthritis that share many features with human RA, and that deletion of Elmo1 during established disease could improve arthritis symptoms and disease resolution. We found that disease resistance is due to specific ELMO1 function in neutrophils, and that loss of ELMO1 significantly attenuated neutrophil activation and migration (induced by chemokines involved in arthritis) and reduced neutrophil mobilization to the joints. Circulating Elmo1–/– neutrophils had reduced cell surface levels of the tethering molecule CD62L, and reduced chemokine-induced exposure of the adhesion/migration-promoting integrin CD11b. These data suggest that ELMO1 function may be required for multiple steps of the neutrophil recruitment cascade to enhance neutrophil recruitment into joints. Surprisingly, loss of ELMO1 did not impair neutrophil recruitment and function elicited by bacterial stimuli, indicating that therapeutic targeting of ELMO1 could maintain normal pathogen clearance. Finally, the RA-associated SNP rs11984075, located in an intron of the ELMO1 gene, correlates with increased ELMO1 protein and elevated CD62L in neutrophils, suggesting that RA patients with SNP rs11984075 could benefit from therapeutic approaches targeting ELMO1. We hypothesize that ELMO1 contributes to tissue/stimulus-specific neutrophil recruitment and pathology in inflammatory arthritis. In this proposal, we will address three specific aims: 1. Test if ELMO1 is required for stimulus- or tissue- specific neutrophil recruitment. 2. Test if ELMO1 promotes neutrophil adhesion through CD62L/L-selectin, and 3. Identify the mechanism by which ELMO1 SNP rs11984075 elevates protein levels and test an inhibitor of ELMO1 in arthritis. This proposal is significant because it will further our understanding of the role of ELMO1 in neutrophil-mediated pathology in rheumatoid arthritis and could lead to the discovery of new diagnostic tools and therapeutic strategies. Our proposal is innovative because it will advance new concepts in ELMO1 biology and will generate new tools for the scientific community and for studying neutrophil functions.
了解在关节炎中驱动中性粒细胞介导病理的分子级联

项目成果

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Sanja Arandjelovic其他文献

Sanja Arandjelovic的其他文献

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{{ truncateString('Sanja Arandjelovic', 18)}}的其他基金

Impact of phagocytosis on amyloid beta-induced pathology
吞噬作用对β淀粉样蛋白诱导的病理学的影响
  • 批准号:
    10724363
  • 财政年份:
    2023
  • 资助金额:
    $ 49.4万
  • 项目类别:
The Role of Efferocytosis in Inflammatory Arthritis
胞吞作用在炎症性关节炎中的作用
  • 批准号:
    10572853
  • 财政年份:
    2023
  • 资助金额:
    $ 49.4万
  • 项目类别:

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