Mechanisms of TL1A-driven Paneth Cell dysfunction in IBD

IBD 中 TL1A 驱动的潘氏细胞功能障碍的机制

基本信息

  • 批准号:
    10077845
  • 负责人:
  • 金额:
    $ 38.25万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2020
  • 资助国家:
    美国
  • 起止时间:
    2020-01-01 至 2023-12-31
  • 项目状态:
    已结题

项目摘要

PROJECT SUMMARY ABSTRACT Inflammatory bowel diseases (IBD) are chronic relapsing diseases of the gastrointestinal tract believed to be the result of complex interactions between genetic susceptibility and severity genes, the microbial environment, and a dysregulated innate and adaptive immune response against commensal micro-organisms. Paneth cells (PC) are specialized small bowel (SB) epithelial cells that constitutively produce anti-microbial proteins and are important in intestinal homeostasis. Abnormal PC morphology is observed in patients with Crohn’s disease (CD) and in mice with gene deletions in autophagy and unfolded protein response (UPR) pathways. Mice with PC-specific deletions in UPR and autophagy pathways develop early and severe SB inflammation. PC morphologic abnormalities precede onset of ileitis, implicating altered PC biology as central to the pathogenesis and severity of SB CD; yet the cell-extrinsic signals driving these abnormalities are undefined. TNFSF15/(TL1A) is an IBD susceptibility and severity locus and we have previously reported the relationship of a TNFSF15 risk genotype and increased expression of TL1A in peripheral monocytes and in non- inflamed SB CD. In translational studies, we also reported the association between this risk genotype and severe forms of SB CD including fibrostenosis that was phenocopied in mice overexpressing TL1A. We have found a significant association between TL1A and abnormal PC morphology. Commensal microbiota are required in TL1A-overexpressing mice to induce ileal inflammation and in wild type mice to induce normal PC maturation and expansion. We developed a novel stem cell micro-engineered chip model of functional human PC, we showed TL1A directly alters the PC phenotype by inducing diffused and disordered lysozyme granule morphology recapitulating the abnormal PC phenotypes in SB CD with high mucosal expression of TL1A. Evidence that serum levels of IBD-associated anti-bacterial antibodies are elevated in unaffected family members of patients with IBD and also in members of the military prior to clinical evidence of disease suggests defects in the host-bacterial interface precedes onset of IBD. Loss of response to biologics and disease recurrence may represent elimination of a disease driving cytokine but not the underlying process. If pre- inflammatory PC abnormality can be mitigated/prevented by manipulation of TL1A, which, addresses the microbial-host interface, potentially PC function will reset and IBD may be pre-empted in genetically susceptible individuals, and the combination may also prevent loss of response to existing therapeutics or disease recurrence. The foregoing provides a strong rationale for studying the mechanisms of TL1A-driven changes in PC morphology, maturation, and function in promoting SB inflammation, using our novel murine in vivo and human stem cell in vitro systems that allow for parallel investigations to parse out cellular and molecular interactions simultaneously. Our investigations will reveal additional downstream pathways and molecules and potentially targets for combination therapy.
项目摘要

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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Stephan R. Targan其他文献

Serial 6-mercaptopurine (6-MP) metabolite measurements in combination with dose escalation unmasks an important biochemical explanation for "6-MP resistance"
  • DOI:
    10.1016/s0016-5085(00)85698-x
  • 发表时间:
    2000-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Marla C. Dubinsky;Philip V. Hassard;Lori Y. Kam;Maria T. Abreu;Ernest G. Seidman;Stephan R. Targan;Eric A. Vasiliauskas
  • 通讯作者:
    Eric A. Vasiliauskas
Thioguanine (6-TG): A therapeutic alternative in a subgroup of IBD patients failing 6-mercaptopurine (6-MP)
  • DOI:
    10.1016/s0016-5085(00)85701-7
  • 发表时间:
    2000-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Marla C. Dubinsky;Philip V. Hassard;Maria T. Abreu;Lori Y. Kam;Ernest G. Seidman;Stephan R. Targan;Eric A. Vasiliauskas
  • 通讯作者:
    Eric A. Vasiliauskas
Sa1879 - UBE2L3, ANCA, ASCA, and CBIR1 are Associated with Mechanisms of non-Response to Anti-TNF in IBD Patients with Adequate Drug Levels
  • DOI:
    10.1016/s0016-5085(17)31514-7
  • 发表时间:
    2017-04-01
  • 期刊:
  • 影响因子:
  • 作者:
    Leilei Zhu;Gil Melmed;Xiaofei Yan;Talin Haritunians;David Q. Shih;Eric Vasiliauskas;Andrew Ippoliti;Shervin Rabizadeh;Namita Singh;Stephan R. Targan;Zhenqiu Liu;Dalin Li;Dermot McGovern
  • 通讯作者:
    Dermot McGovern
Sa131 DEVELOPMENT OF A PERSONALIZED MODEL OF INTESTINAL FIBROSIS USING HUMAN INTESTINAL ORGANOIDS DERIVED FROM INDUCED PLURIPOTENT STEM CELLS
  • DOI:
    10.1016/s0016-5085(21)01744-3
  • 发表时间:
    2021-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Hannah Q. Estrada;Shachi Patel;Shervin Rabizadeh;Stephan R. Targan;Robert J. Barrett
  • 通讯作者:
    Robert J. Barrett
Su1750 Transethnic Fine-Mapping of the <em>IL12B</em> Locus Identifies Two Independent Signals Associated With IBD Susceptibility and Disease Behaviors
  • DOI:
    10.1016/s0016-5085(13)61727-8
  • 发表时间:
    2013-05-01
  • 期刊:
  • 影响因子:
  • 作者:
    Yoichi Kakuta;Marla Dubinsky;Dalin Li;Kyuyoung Song;Suk-Kyun Yang;Byong Duk Ye;Stephen S. Rich;Suna Onengut-Gumuscu;Esther A. Torres;Deepa Panikkath;Talin Haritunians;Stephan R. Targan;Jerome I. Rotter;Kent D. Taylor;Dermot P. McGovern
  • 通讯作者:
    Dermot P. McGovern

Stephan R. Targan的其他文献

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{{ truncateString('Stephan R. Targan', 18)}}的其他基金

Mechanisms of TL1A-driven Paneth Cell dysfunction in IBD
IBD 中 TL1A 驱动的潘氏细胞功能障碍的机制
  • 批准号:
    10539302
  • 财政年份:
    2020
  • 资助金额:
    $ 38.25万
  • 项目类别:
Mechanisms of TL1A-driven Paneth Cell dysfunction in IBD
IBD 中 TL1A 驱动的潘氏细胞功能障碍的机制
  • 批准号:
    10311509
  • 财政年份:
    2020
  • 资助金额:
    $ 38.25万
  • 项目类别:
Molecular characterization of the role of RNASET2 in Severe Crohn's Disease
RNASET2 在严重克罗恩病中作用的分子表征
  • 批准号:
    10021036
  • 财政年份:
    2019
  • 资助金额:
    $ 38.25万
  • 项目类别:
Molecular characterization of the role of RNASET2 in Severe Crohn's Disease
RNASET2 在严重克罗恩病中作用的分子表征
  • 批准号:
    10226172
  • 财政年份:
    2019
  • 资助金额:
    $ 38.25万
  • 项目类别:
Role of TRIF-Dependent TLR Signaling in Intestinal Mucosa
TRIF 依赖性 TLR 信号转导在肠粘膜中的作用
  • 批准号:
    10225616
  • 财政年份:
    2012
  • 资助金额:
    $ 38.25万
  • 项目类别:
INFLAMMATORY BOWEL DISEASE CENTER: CLINICAL DATA REPOSITORY - TISSUE PROCUREMENT
炎症性肠病中心:临床数据存储库 - 组织采购
  • 批准号:
    8174459
  • 财政年份:
    2009
  • 资助金额:
    $ 38.25万
  • 项目类别:
IBD: Mucosa Specific Regulation of IFN-gamma Production
IBD:粘膜对 IFN-γ 产生的特异性调节
  • 批准号:
    7921223
  • 财政年份:
    2009
  • 资助金额:
    $ 38.25万
  • 项目类别:
INFLAMMATORY BOWEL DISEASE CENTER: CLINICAL DATA REPOSITORY - TISSUE PROCUREMENT
炎症性肠病中心:临床数据存储库 - 组织采购
  • 批准号:
    7952200
  • 财政年份:
    2008
  • 资助金额:
    $ 38.25万
  • 项目类别:
CORE--TISSUE PROCUREMENT & DATA ANALYSIS & SERUM ANALYSIS
核心——纸巾采购
  • 批准号:
    7487329
  • 财政年份:
    2007
  • 资助金额:
    $ 38.25万
  • 项目类别:
INFLAMMATORY BOWEL DISEASE CENTER: CLINICAL DATA REPOSITORY - TISSUE PROCUREMENT
炎症性肠病中心:临床数据存储库 - 组织采购
  • 批准号:
    7606129
  • 财政年份:
    2007
  • 资助金额:
    $ 38.25万
  • 项目类别:

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