Bifidobacterium bifidum modulation of intestinal barrier and intestinal inflammation

双歧杆菌对肠道屏障和肠道炎症的调节

基本信息

  • 批准号:
    9682782
  • 负责人:
  • 金额:
    $ 25.26万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2018
  • 资助国家:
    美国
  • 起止时间:
    2018-04-20 至 2020-06-30
  • 项目状态:
    已结题

项目摘要

 DESCRIPTION (provided by applicant): Defective intestinal epithelial tight junction (TJ) barrier is a key pathogenic factor of inflammatory bowel disease (IBD) and other inflammatory conditions of the gut. A leaky TJ barrier allows increased intestinal permeation of bacterial antigens that induce inflammatory response. Previous studies have shown that tightening (or re-tightening) of the intestinal TJ barrier prevents the development of intestinal inflammation in both animal models of IBD and in human IBD. However, there are no currently available therapeutic agents that target the intestinal TJ barrier. There is also an important gap in medical knowledge regarding the intracellular processes that can be targeted to induce therapeutic tightening of the intestinal TJ barrier. In this grant application, we intend to 1) introduce a new therapeutic agent that targets the intestinal TJ barrier which can be rapidly advanced for clinical usage; and 2) identify intracellular mechanisms that can be targeted to induce tightening of the intestinal TJ barrier. In our preliminary studies, we tested number of probiotic species/strains that are widely available commercially to identify a single strain, Bifidobacterium bifidum VIII-21 (BB), which causes a marked enhancement in intestinal TJ barrier and has therapeutic efficacy in animal models of IBD. The over-arching goals of this application are to investigate the intestinal TJ barrier augmenting effects of BB and to determine the therapeutic efficacy of BB in animal models of IBD. Based on our compelling preliminary data, we advance a novel hypothesis that BB protects against the development of intestinal inflammation by enhancing and preserving the intestinal TJ barrier; and that BB enhancement and protection of intestinal TJ barrier is mediated by Nod1 signal-transduction pathway activation of occludin gene and suppression of myosin light chain kinase (MLCK) gene. In this grant application, we also challenge 2 well-established scientific paradigms: 1) that Nod1 is a cytoplasmic pattern recognition receptor (PRR); and 2) that the primary cellular target of Nod1 is the activation of NF-κB. We also hypothesize that BB protects against pro-inflammatory cytokine-induced increase in intestinal TJ permeability by Nod1/PPAR- γ mediated suppression (not activation) of NF-κB and MLCK gene. Four inter-linked specific aims are proposed to address above hypotheses: 1) to delineate the role of PRRs in BB-induced augmentation of intestinal epithelial TJ barrier; 2) to delineate the molecular mechanism of BB modulation of intestinal TJ barrier; 3) to delineate the protective mechanism of BB against of pro-inflammatory cytokine-induced increase in intestinal TJ permeability; and 4) to delineate the therapeutic efficacy of BB in anima models of IBD. The successful completion of the proposed studies will help bridge the important gap in scientific knowledge and provide crucial pre-clinical data to support the planned future clinical studies.
 描述(由申请人提供):有缺陷的肠上皮紧密连接(TJ)屏障是炎症性肠病(IBD)和肠道其他炎症性疾病的关键致病因素。渗漏的 TJ 屏障会增加细菌抗原的肠道渗透,从而诱导炎症反应。先前的研究表明,在 IBD 动物模型和人类 IBD 中,收紧(或重新收紧)肠道 TJ 屏障可防止肠道炎症的发生。然而,目前还没有针对肠道 TJ 屏障的治疗药物。医疗方面也存在重要差距 有关细胞内过程的知识,可以针对这些过程来诱导肠道 TJ 屏障的治疗收紧。在本次拨款申请中,我们打算 1) 引入一个新的 靶向肠道 TJ 屏障的治疗剂,可快速推进临床 用法; 2) 确定可靶向诱导肠道 TJ 屏障收紧的细胞内机制。在我们的初步研究中,我们测试了多种商业上广泛使用的益生菌物种/菌株,以确定单一菌株,两歧双歧杆菌 VIII-21 (BB),它能显着增强肠道 TJ 屏障,并在 IBD 动物模型中具有治疗功效。该应用的首要目标是研究 BB 增强肠道 TJ 屏障的作用,并确定 BB 在 IBD 动物模型中的治疗效果。基于我们令人信服的初步数据,我们提出了一个新的假设,即 BB 通过增强和保护肠道 TJ 屏障来防止肠道炎症的发展; BB 增强和保护肠道 TJ 屏障是通过 Nod1 信号转导途径激活 occludin 基因和抑制肌球蛋白轻链激酶 (MLCK) 基因介导的。在本次资助申请中,我们还挑战了 2 个公认的科学范式:1)Nod1 是一种细胞质模式识别受体(PRR); 2) Nod1 的主要细胞靶标是 NF-κB 的激活。我们还假设 BB 通过 Nod1/PPAR-γ 介导的 NF-κB 和 MLCK 基因抑制(而不是激活)来防止促炎细胞因子诱导的肠道 TJ 通透性增加。提出了四个相互关联的具体目标来解决上述假设:1)描述 PRR 在 BB 诱导的肠上皮 TJ 屏障增强中的作用; 2)阐明BB调节肠道TJ屏障的分子机制; 3) 阐明 BB 对促炎细胞因子诱导的肠道 TJ 通透性增加的保护机制; 4) 描述 BB 在 IBD 动物模型中的治疗效果。拟议研究的成功完成将有助于弥合科学知识方面的重要差距,并提供重要的临床前数据来支持计划的未来临床研究。

项目成果

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THOMAS Y MA其他文献

THOMAS Y MA的其他文献

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{{ truncateString('THOMAS Y MA', 18)}}的其他基金

Intestinal Barrier, Probiotic Bacteria, and the Gut-Liver Axis
肠道屏障、益生菌和肠-肝轴
  • 批准号:
    10316171
  • 财政年份:
    2019
  • 资助金额:
    $ 25.26万
  • 项目类别:
Intestinal Barrier, Probiotic Bacteria, and the Gut-Liver Axis
肠道屏障、益生菌和肠-肝轴
  • 批准号:
    10543991
  • 财政年份:
    2019
  • 资助金额:
    $ 25.26万
  • 项目类别:
Intestinal Barrier, Probiotic Bacteria, and the Gut-Liver Axis
肠道屏障、益生菌和肠-肝轴
  • 批准号:
    9895788
  • 财政年份:
    2019
  • 资助金额:
    $ 25.26万
  • 项目类别:
Bifidobacterium bifidum modulation of intestinal barrier and intestinal inflammation
双歧杆菌对肠道屏障和肠道炎症的调节
  • 批准号:
    9751834
  • 财政年份:
    2018
  • 资助金额:
    $ 25.26万
  • 项目类别:
Regulation of Intestinal Epithelial Tight Junction Barrier
肠上皮紧密连接屏障的调节
  • 批准号:
    8244940
  • 财政年份:
    2011
  • 资助金额:
    $ 25.26万
  • 项目类别:
Regulation of Intestinal Epithelial Tight Junction Barrier
肠上皮紧密连接屏障的调节
  • 批准号:
    8141671
  • 财政年份:
    2011
  • 资助金额:
    $ 25.26万
  • 项目类别:
Interleukin-1 Beta Modulation of Intestinal Tight Junction Barrier
Interleukin-1 Beta 调节肠道紧密连接屏障
  • 批准号:
    7806656
  • 财政年份:
    2009
  • 资助金额:
    $ 25.26万
  • 项目类别:
Interleukin-1 Beta Modulation of Intestinal Tight Junction Barrier
Interleukin-1 Beta 调节肠道紧密连接屏障
  • 批准号:
    8098031
  • 财政年份:
    2009
  • 资助金额:
    $ 25.26万
  • 项目类别:
Interleukin-1 Beta Modulation of Intestinal Tight Junction Barrier
Interleukin-1 Beta 调节肠道紧密连接屏障
  • 批准号:
    7650889
  • 财政年份:
    2009
  • 资助金额:
    $ 25.26万
  • 项目类别:
Interleukin-1 Beta Modulation of Intestinal Tight Junction Barrier
Interleukin-1 Beta 调节肠道紧密连接屏障
  • 批准号:
    8290490
  • 财政年份:
    2009
  • 资助金额:
    $ 25.26万
  • 项目类别:

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新菌株B. bifidum 2021通过激活巨噬细胞TLR4/MyD88/NF-κB通路增强PD-1单抗治疗结直肠癌敏感性的效应及分子机制研究
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