Integration of mononuclear phagocytes into the human gastrointestinal GOFlowChip for investigation of luminal antigen sampling

将单核吞噬细胞整合到人胃肠道 GOFlowChip 中用于腔内抗原采样研究

基本信息

  • 批准号:
    9893635
  • 负责人:
  • 金额:
    $ 56.54万
  • 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:
    2019-09-30 至 2024-06-30
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY This project will develop novel in vitro models of the human gastrointestinal (GI) tract for understanding natural cellular responses to microbes and the induction of immune tolerance and activation. The development of gastrointestinal organoids, 3-D permanent cultures of complex primary epithelial cell populations embedded in an extracellular matrix, has revolutionized research in gastrointestinal development, microbiology and immunology in the past 5 years. For our project, we have assembled a trans-disciplinary team of investigators with expertise in bioengineering (Wilking, Chang), immunology (Bimczok, Jutila), and human microbiome research (Walk) to significantly advance 3-D gut organoid-microbiome co-culture systems. Our team has recently established a millifluidic gut-on-a chip-platform, the GoFlowChip, that recapitulates luminal and basal flow in human intestinal organoids. In parallel investigations, we have established co-cultures of primary human monocyte-derived DCs and human gastric spheroids that we have successfully infected with H. pylori. Here, we seek to leverage the unique capabilities of our two models and combine them into a single analytical platform to study antigen sampling from the gastrointestinal lumen for the induction of adaptive mucosal immunity or tolerance. Specifically, we seek to define and quantify the contributions of candidate mechanisms including transepithelial dendrite formation and Fc-receptor-dependent transcytosis that enable mononuclear phagocytes (MNPs) to acquire luminal antigens. We hypothesize that distinct mechanisms of MNP antigen acquisition are reproduced and can be quantitatively analyzed using the GOFlowChip platform and that colonizing bacteria and fluid dynamics regulate epithelial antigen transport. To test our hypotheses, we will (1) Develop and validate a chip-based organoid-DC co-culture system with luminal and basolateral flow capacity. (2) Quantify the net effect of biologic complexity on GI organoid biology and MNP interaction. (3) Elucidate the mechanisms involved in bacterial antigen sampling from the gastrointestinal lumen by human MNPs. This approach will enable us to optimize our integrated GoFlowChip co-culture system as a powerful new tool for the field for studies on vaccine or drug delivery and on the impact of intestinal microbiota on antigen sampling. The proposed research is conceptually innovative, because it integrates all three necessary cell types (epithelial, microbial, and immune) involved in mucosal host-microbe interactions. The GoFlowChip platform is technologically innovative, because it replicates a complex, oxygen-utilizing epithelium and a microbially colonized lumen, is the first to incorporate fluidics into 3-D organoid cultures, and reproduces the intimate interactions that naturally occur between the gastrointestinal epithelium and sentinel MNPs. The proposed research is significant, because it will provide an incredibly powerful new tool to address fundamental, mechanistic questions in human mucosal biology, microbiology, and immunology in the context of human health and disease.
项目总结

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)

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Diane Bimczok其他文献

Diane Bimczok的其他文献

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{{ truncateString('Diane Bimczok', 18)}}的其他基金

Mechanisms of antiviral immunity and tolerance in the intestinal epithelium of Jamaican Fruit Bats
牙买加果蝠肠上皮的抗病毒免疫和耐受机制
  • 批准号:
    10592671
  • 财政年份:
    2023
  • 资助金额:
    $ 56.54万
  • 项目类别:
PREP-MT: Providing Research Education for Postbaccalaureate Trainees in Montana
PREP-MT:为蒙大拿州的学士后学员提供研究教育
  • 批准号:
    10772282
  • 财政年份:
    2023
  • 资助金额:
    $ 56.54万
  • 项目类别:
Defining receptor-ligand interactions in gastric epithelial immunosurveillance
定义胃上皮免疫监视中的受体-配体相互作用
  • 批准号:
    10652599
  • 财政年份:
    2022
  • 资助金额:
    $ 56.54万
  • 项目类别:
Defining receptor-ligand interactions in gastric epithelial immunosurveillance
定义胃上皮免疫监视中的受体-配体相互作用
  • 批准号:
    10517171
  • 财政年份:
    2022
  • 资助金额:
    $ 56.54万
  • 项目类别:
Integration of mononuclear phagocytes into the human gastrointestinal GOFlowChip for investigation of luminal antigen sampling
将单核吞噬细胞整合到人胃肠道 GOFlowChip 中用于腔内抗原采样研究
  • 批准号:
    10286736
  • 财政年份:
    2021
  • 资助金额:
    $ 56.54万
  • 项目类别:
Integration of mononuclear phagocytes into the human gastrointestinal GOFlowChip for investigation of luminal antigen sampling
将单核吞噬细胞整合到人胃肠道 GOFlowChip 中用于腔内抗原采样研究
  • 批准号:
    10318511
  • 财政年份:
    2020
  • 资助金额:
    $ 56.54万
  • 项目类别:
Using the GoFlowChip to understand SARS-CoV-2 infection of the gastrointestinal mucosa of humans and bats
使用 GoFlowChip 了解人类和蝙蝠胃肠粘膜的 SARS-CoV-2 感染
  • 批准号:
    10166517
  • 财政年份:
    2020
  • 资助金额:
    $ 56.54万
  • 项目类别:
Integration of mononuclear phagocytes into the human gastrointestinal GOFlowChip for investigation of luminal antigen sampling
将单核吞噬细胞整合到人胃肠道 GOFlowChip 中用于腔内抗原采样研究
  • 批准号:
    10263208
  • 财政年份:
    2019
  • 资助金额:
    $ 56.54万
  • 项目类别:
Integration of mononuclear phagocytes into the human gastrointestinal GOFlowChip for investigation of luminal antigen sampling
将单核吞噬细胞整合到人胃肠道 GOFlowChip 中用于腔内抗原采样研究
  • 批准号:
    10019549
  • 财政年份:
    2019
  • 资助金额:
    $ 56.54万
  • 项目类别:
Integration of mononuclear phagocytes into the human gastrointestinal GOFlowChip for investigation of luminal antigen sampling
将单核吞噬细胞整合到人胃肠道 GOFlowChip 中用于腔内抗原采样研究
  • 批准号:
    10461114
  • 财政年份:
    2019
  • 资助金额:
    $ 56.54万
  • 项目类别:

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