Understanding the role of myeloid cells in ozone-induced airway disease

了解骨髓细胞在臭氧引起的气道疾病中的作用

基本信息

  • 批准号:
    10091437
  • 负责人:
  • 金额:
    $ 50.11万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2019
  • 资助国家:
    美国
  • 起止时间:
    2019-02-01 至 2025-01-31
  • 项目状态:
    未结题

项目摘要

Project Summary Nearly one-third of the United States population lives in areas with unhealthy levels of ambient ozone. Since increased ozone levels are associated with respiratory problems in children, elderly, and patients with pre- existing cardiopulmonary diseases, elucidating the cellular and molecular mechanisms of ozone-induced lung injury is highly significant in terms of formulating therapeutic strategies. Ozone results in predominantly Type 2 (Th2) inflammatory responses including eosinophilic inflammation and mucous cell metaplasia that are also the hallmarks of allergic asthma. While it is understood that interleukin 4 receptor α (IL4Rα, a common receptor for IL4 and IL13) is essential for Th2 inflammatory responses, what is not clear is which IL4Rα-bearing cell-type is indispensable for various outcomes in Th2-associated diseases. Lack of such knowledge is a major obstacle in the development of effective therapeutic strategies, because, without it, the IL4Rα inhibitors will remain non- specific and not fully effective, as is the case with ongoing clinical trials with IL4Rα inhibitors. Our central hypothesis is that myeloid cell-specific Type II IL4R is essential for ozone-induced granulocyte recruitment and the pathological manifestation of Th2-associated responses, and that the IL4Rα-bearing myeloid cells release IL4 that regulates downstream IL4Rα signaling through Type I IL4Rα on non-myeloid cells. The overall objective of this proposal is to delineate the myeloid cell-specific role of IL4Rα signaling in ozone- induced airway disease and to identify myeloid-IL4Rα-mediated soluble and vesicle-bound mediators of ozone-induced inflammation in airspaces. In aim 1 we will employ myeloid-, macrophage-, and cDC-specific IL4Rα deficient mice or myeloid-only-, macrophage-only-, and cDC-only-IL4Rα sufficient mice, to investigate the role of myeloid-, macrophage-, and cDC-specific IL4Rα in ozone-induced granulocyte recruitment. In aim 2, we will test our hypothesis that mye-specific IL4Rα is required for IL4 production that, in turn, mediates the downstream responses through Type I IL4Rα-receptor on non-myeloid cells. Furthermore, a comprehensive analysis of bronchoalveolar lavage, both fluid and the vesicular fraction, will be performed to reveal the identity of additional mediators released from IL4Rα-bearing myeloid and non-myeloid cells. In aim 3, The myeloid- specific IL4Rα deficient mice (males vs females; neonates vs adults vs aged) will be exposed to ozone as well as ozone superimposed with mixed allergens. This aim will reveal gender- and age-specific role of myeloid IL4Rα in asthma outcomes. The findings from our studies will have a transformative impact on the mechanistic understanding of the pathophysiology of ozone-induced airway disease. Eventually, these findings may be applied towards the development of cell-specific therapeutics against ozone-induced as well as other Th2- associated diseases.
项目总结

项目成果

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Yogesh Saini其他文献

Yogesh Saini的其他文献

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{{ truncateString('Yogesh Saini', 18)}}的其他基金

Pathogenesis of mucous cell metaplasia in ozone-exposed airways
臭氧暴露气道粘液细胞化生的发病机制
  • 批准号:
    10598728
  • 财政年份:
    2023
  • 资助金额:
    $ 50.11万
  • 项目类别:
Modulation of RNA Binding Proteins in Xenobiotic-induced Hepatotoxicity
RNA 结合蛋白在异生素诱导的肝毒性中的调节
  • 批准号:
    10587498
  • 财政年份:
    2023
  • 资助金额:
    $ 50.11万
  • 项目类别:
Myeloid Cell Signaling in Allergic Asthma
过敏性哮喘中的骨髓细胞信号转导
  • 批准号:
    10078643
  • 财政年份:
    2019
  • 资助金额:
    $ 50.11万
  • 项目类别:
Myeloid Cell Signaling in Allergic Asthma
过敏性哮喘中的骨髓细胞信号转导
  • 批准号:
    10341066
  • 财政年份:
    2019
  • 资助金额:
    $ 50.11万
  • 项目类别:
Understanding the role of myeloid cells in ozone-induced airway disease
了解骨髓细胞在臭氧引起的气道疾病中的作用
  • 批准号:
    10337211
  • 财政年份:
    2019
  • 资助金额:
    $ 50.11万
  • 项目类别:
Pulmonary Immunopathology
肺部免疫病理学
  • 批准号:
    10341063
  • 财政年份:
    2019
  • 资助金额:
    $ 50.11万
  • 项目类别:
Pulmonary Immunopathology
肺部免疫病理学
  • 批准号:
    10588207
  • 财政年份:
    2019
  • 资助金额:
    $ 50.11万
  • 项目类别:

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