Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments

离散肠道微环境中 T 细胞功能的核受体控制

基本信息

  • 批准号:
    10757138
  • 负责人:
  • 金额:
    $ 20.62万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-09-23 至 2026-08-31
  • 项目状态:
    未结题

项目摘要

Project Summary The gut is a central immunological organ, where host-microbe interactions shape immune tolerance and inflammation, both locally and systemically. Yet prevailing immunological views conflate the two distinct organs that comprise the gut—small and large intestine (or SI and LI)—which impedes more robust understanding of mucosal immune regulation, and misses opportunities to develop safer, more targeted therapies for human inflammatory bowel diseases (IBDs). The premise of this application, founded on recent discoveries from, and synergy between, the two PIs (Sundrud, Weaver), is that mucosal CD4+ T cells use distinct sets of nuclear receptors (NRs) in the SI and LI to interface with divergent classes of host- and microbe-derived metabolites, respectively. Recent work from the Sundrud lab establishes that Foxp3- T effector (Teff) subsets—Th1, Th17 cells—use a NR with no previously known immunological function, the constitutive androstane receptor (CAR/Nr1i3), to direct a ‘hepatocyte-like’ transcriptional response to contend with potentially cytotoxic bile acid (BA) concentrations in the SI. A large gradient of BAs exists between the SI (millimolar) and LI (micromolar) due to ‘enterohepatic’ circulation—primary BAs synthesized in the liver, stored in the gallbladder, and secreted post- prandially into the duodenum are actively reabsorbed by specialized enterocytes in the ileum for portal recirculation to the liver. Because BAs are lipophilic, they can be toxic and pro-inflammatory in enterohepatic tissues; a host of nuclear receptors—including CAR—have evolved to suppress BA toxicity in hepatocytes and enterocytes. Our data suggest that enterohepatic circulation creates a uniquely harsh SI microenvironment to which infiltrating T cells must adapt to maintain tolerance and tissue homeostasis. The LI, by contrast, harbors 103-107 times more bacteria than the SI, and ~1000-fold less BAs. Accordingly, microbes and their metabolites— short chain fatty acids (SCFAs; e.g., butyrate), secondary BAs (produced via microbial metabolism of residual primary BAs)—become central to immune regulation in the LI. SCFAs inhibit histone deacetylase enzymes (HDACs) and stabilize Foxp3 gene expression in peripherally-induced T regulatory cells (iTregs), whereas secondary BAs promote LI Treg maintenance through another NR, vitamin D receptor (VDR). Thus, while antigens from the enteric flora are required for priming both pro- and anti-inflammatory T cell responses throughout the intestinal tract, we hypothesize that marked differences in the abundance of bugs and bile in the SI vs. LI establish consequential metabolite gradients that are sensed by different NRs to instruct compartmentalized T cell regulatory functions. We test this hypothesis through complementary, but not inter- dependent, Aims, leveraging new mouse models, as well as a library of recombinant protein-based NR activity assays, to define the mechanisms governing the transcriptional regulation, biochemical activation, and downstream cellular functions of CAR (in SI Teff cells) and VDR (in LI iTreg cells). Successful completion of these Aims will establish new biological paradigms and inform more precise approaches to treat human IBDs.
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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Mark Scott Sundrud其他文献

Mark Scott Sundrud的其他文献

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{{ truncateString('Mark Scott Sundrud', 18)}}的其他基金

Bile acid-dependent T cell regulation in the intestine
肠道内胆汁酸依赖性 T 细胞调节
  • 批准号:
    10767546
  • 财政年份:
    2023
  • 资助金额:
    $ 20.62万
  • 项目类别:
Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments
离散肠道微环境中 T 细胞功能的核受体控制
  • 批准号:
    10493280
  • 财政年份:
    2021
  • 资助金额:
    $ 20.62万
  • 项目类别:
Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments
离散肠道微环境中 T 细胞功能的核受体控制
  • 批准号:
    10391961
  • 财政年份:
    2021
  • 资助金额:
    $ 20.62万
  • 项目类别:
Transcript-selective translational control of Th17 cell development and function
Th17 细胞发育和功能的转录选择性翻译控制
  • 批准号:
    10373280
  • 财政年份:
    2021
  • 资助金额:
    $ 20.62万
  • 项目类别:
Transcript-selective translational control of Th17 cell development and function
Th17 细胞发育和功能的转录选择性翻译控制
  • 批准号:
    10591695
  • 财政年份:
    2021
  • 资助金额:
    $ 20.62万
  • 项目类别:
Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments
离散肠道微环境中 T 细胞功能的核受体控制
  • 批准号:
    10591677
  • 财政年份:
    2021
  • 资助金额:
    $ 20.62万
  • 项目类别:
Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments
离散肠道微环境中 T 细胞功能的核受体控制
  • 批准号:
    10685603
  • 财政年份:
    2021
  • 资助金额:
    $ 20.62万
  • 项目类别:
Transcript-selective translational control of Th17 cell development and function
Th17 细胞发育和功能的转录选择性翻译控制
  • 批准号:
    10753258
  • 财政年份:
    2021
  • 资助金额:
    $ 20.62万
  • 项目类别:
Bile acid-dependent T cell regulation in the intestine
肠道内胆汁酸依赖性 T 细胞调节
  • 批准号:
    10591659
  • 财政年份:
    2019
  • 资助金额:
    $ 20.62万
  • 项目类别:

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Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments
离散肠道微环境中 T 细胞功能的核受体控制
  • 批准号:
    10493280
  • 财政年份:
    2021
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  • 项目类别:
Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments
离散肠道微环境中 T 细胞功能的核受体控制
  • 批准号:
    10391961
  • 财政年份:
    2021
  • 资助金额:
    $ 20.62万
  • 项目类别:
Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments
离散肠道微环境中 T 细胞功能的核受体控制
  • 批准号:
    10591677
  • 财政年份:
    2021
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    $ 20.62万
  • 项目类别:
Nuclear Receptor Control of T Cell Function in Discrete Intestinal Microenvironments
离散肠道微环境中 T 细胞功能的核受体控制
  • 批准号:
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