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):肠上皮紧密连接(TJ)屏障缺陷是炎症性肠病(IBD)和肠道其他炎症性疾病的关键致病因素。TJ屏障的渗漏会增加细菌抗原的肠道渗透,从而诱导炎症反应。先前的研究已经表明,收紧(或重新收紧)肠TJ屏障可以防止IBD动物模型和人类IBD中肠道炎症的发展。然而,目前还没有靶向肠TJ屏障的治疗剂。在医疗方面也存在重要差距 关于可以靶向诱导肠TJ屏障的治疗性收紧的细胞内过程的知识。在这项拨款申请中,我们打算1)引入一个新的 靶向肠TJ屏障的治疗剂,其可以快速推进用于临床 使用;和2)鉴定可以靶向诱导肠TJ屏障收紧的细胞内机制。在我们的初步研究中,我们测试了大量的益生菌物种/菌株,这些益生菌物种/菌株在商业上广泛可用,以鉴定单一菌株两歧双歧杆菌VIII-21(BB),其引起肠道TJ屏障的显著增强,并且在IBD的动物模型中具有治疗功效。本申请的总体目标是研究BB的肠TJ屏障增强作用并确定BB在IBD动物模型中的治疗功效。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Nod 1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。在这项拨款申请中,我们还挑战了两个公认的科学范式:1)Nod 1是一种细胞质模式识别受体(PRR); 2)Nod 1的主要细胞靶点是NF-κB的激活。我们还假设BB通过Nod 1/PPAR- γ介导的NF-κB和MLCK基因的抑制(而非激活)来防止促炎性丝氨酸诱导的肠TJ通透性增加。本研究拟从以下四个方面来探讨上述假说:1)阐明PRRs在BB诱导的肠上皮TJ屏障增强中的作用; 2)阐明BB调节肠TJ屏障的分子机制; 3)阐明BB对促炎性激素诱导的肠TJ通透性增加的保护机制; 4)观察BB对IBD动物模型的治疗作用。拟议研究的成功完成将有助于弥合科学知识的重要差距,并提供关键的临床前数据,以支持计划的未来临床研究。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

THOMAS Y MA其他文献

THOMAS Y MA的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ 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:

相似国自然基金

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
  • 批准号:
    82203048
  • 批准年份:
    2022
  • 资助金额:
    30 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Elucidation of mechanisms for human-microbiome symbiosis mediated by the sulfated mucin glycan-terminal structures
阐明硫酸化粘蛋白聚糖末端结构介导的人类微生物组共生机制
  • 批准号:
    23K05009
  • 财政年份:
    2023
  • 资助金额:
    $ 25.26万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Mechanism of recovery in the gut microbiome: Multivariate analysis of the effects of antibiotic disturbance and probiotics
肠道微生物群的恢复机制:抗生素干扰和益生菌影响的多变量分析
  • 批准号:
    19J14598
  • 财政年份:
    2019
  • 资助金额:
    $ 25.26万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Functional analysis and application of sulfoglycosidase from mucin-assimilating bacteria
粘蛋白同化菌磺基糖苷酶的功能分析及应用
  • 批准号:
    19K05789
  • 财政年份:
    2019
  • 资助金额:
    $ 25.26万
  • 项目类别:
    Grant-in-Aid for Scientific Research (C)
Engineering a Small Intestinal Microbiome to Evaluate Food Additive Exposure
设计小肠微生物组来评估食品添加剂暴露
  • 批准号:
    10430190
  • 财政年份:
    2018
  • 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:
Engineering a Small Intestinal Microbiome to Evaluate Food Additive Exposure
设计小肠微生物组来评估食品添加剂暴露
  • 批准号:
    10215530
  • 财政年份:
    2018
  • 资助金额:
    $ 25.26万
  • 项目类别:
Functional analysis and application studies of gut microbe-derived sulfoglycosidase and sulfated mucin in symbiosis
肠道微生物磺基糖苷酶与硫酸化粘蛋白共生的功能分析及应用研究
  • 批准号:
    17K17820
  • 财政年份:
    2017
  • 资助金额:
    $ 25.26万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
低酸素環境下におけるプロバイオティクス乳酸菌の腸炎抑制作用の検証
低氧环境下益生菌乳酸菌抑制肠道炎症作用的验证
  • 批准号:
    14J06559
  • 财政年份:
    2014
  • 资助金额:
    $ 25.26万
  • 项目类别:
    Grant-in-Aid for JSPS Fellows
Sulfur-containing compounds biosynthesis in Bifidobacterium bifidum
两歧双歧杆菌中含硫化合物的生物合成
  • 批准号:
    24780075
  • 财政年份:
    2012
  • 资助金额:
    $ 25.26万
  • 项目类别:
    Grant-in-Aid for Young Scientists (B)
Mechanism of Activation of Probiotic Bifidobacteria by Prebiotic Milk Glycans
益生元乳聚糖激活益生菌双歧杆菌的机制
  • 批准号:
    8822837
  • 财政年份:
    2012
  • 资助金额:
    $ 25.26万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了