Microbe dependent mechanisms that antagonize intestinal injury repair

拮抗肠道损伤修复的微生物依赖性机制

基本信息

  • 批准号:
    10748588
  • 负责人:
  • 金额:
    $ 5.27万
  • 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:
    2023-06-01 至 2027-05-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY Debaryomyces hansenii is a fungal member of the gut microbiome and is present within inflamed regions of the intestine in Crohn Disease patients. Patient-derived strains of D. hansenii prolong wound healing in mouse chemical and mechanical intestinal injury models. Mechanisms of pathogenicity of D. hansenii are not well understood, though macrophages are a key effector cell type in the delayed wound healing phenotype. The objective of the proposed work is to define mechanisms of innate host response to D. hansenii using in vitro macrophage models and define microbial mechanisms of impaired wound repair using in vivo models of intestinal injury. Our preliminary data visualizing phagocytosed D. hansenii with transmission electron microscopy and cytological staining demonstrate certain macrophages phagocytose and are unable to clear D. hansenii. Macrophages that do not clear D. hansenii also do not produce TNF-α in response to D. hansenii. In aim 1, I test the hypothesis that TNF-α supports macrophages clearance of phagocytosed D. hansenii and identify the pattern recognition receptors responsible for TNF-α production. In aim 2, I examine microbial morphologic-transitions as an immune evasion mechanism in vitro and in vivo. My preliminary data suggest that vegetative D. hansenii yeast induce more potent pro-inflammatory cytokine production than spores of D. hansenii, and spores persist within macrophage cell lines in vitro. This project will define microbial mechanisms that permit D. hansenii persistence within the intestine and antagonism of injury repair. Successful completion of these aims will define mechanisms of host-response to D. hansenii and microbial-evasion of macrophage clearance that will lead the identification of novel therapeutic targets for treating the subset of Crohn Disease patients with tissue associated D. hansenii.
项目总结

项目成果

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Kevin Newhall的其他文献

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