The Role of TNFSF14 (LIGHT) In Preventing Severe Colitis

TNFSF14 (LIGHT) 在预防严重结肠炎中的作用

基本信息

  • 批准号:
    8566127
  • 负责人:
  • 金额:
    $ 27.41万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
  • 资助国家:
    美国
  • 起止时间:
  • 项目状态:
    未结题

项目摘要

LIGHT is a member of the tumor necrosis factor super family that engages two receptors, the lymphotoxin B receptor (LTBR) and the herpes virus entry mediator (HVEM). Over expression of LIGHT by transgenic mouse T cells causes colitis. We have made the surprising observation, however, that the absence of LIGHT expression in immune deficient Rag-/- mice leads to increased colitis in the T cell transfer model. The experiments in this application are designed to understand the surprising anti-inflammatory role of LIGHT expression in preventing severe colitis. Our preliminary data indicate that LIGHT acts in the innate Immune system by binding to the LTBR. Based on our data and published literature, we propose that LIGHT expression by macrophages acts on the LTBR also expressed by these cells to promote their apoptosis, thereby limiting inflammation. We will use a combination of Immunologic and genetic methods to test our hypothesis and to understand the unexpected role of LIGHT expression by cells other than T lymphocytes in the prevention of severe colitis. In aim 1, we will characterize the immunopathogenesis of the severe colitis in Rag-/- recipient mice deficient for LIGHT. We also will analyze the effects of reduced LIGHT expression in models of colitis that involve only innate immune cells, and we will determine if the absence of LIGHT affects apoptosis of some cell type, a known outcome of the LIGHT:LTBR Interaction. In aim 2 we will confirm (or refute) the preliminary data indicating that prevention of severe colitis is dependent upon LTBR expression. In aim 3 we will determine if soluble LIGHT Is required, as It Is In concanavalin A-induced liver damage. Experiments in aim 4 will determine the critical cell types that must express LIGHT and its receptor in order to prevent severe disease. Finally, experiments in Aim 5 will bridge the findings from mouse models to the study of patients. We will investigate TNFSF14 (LIGHT) gene polymorphisms that affect colitis pathogenesis In IBD patients, to determine if these are related either to LIGHT expression levels or to the ability of LIGHT to bind its receptors. Therefore, the experiments in this project should lead to great Insights into the mechanism underlying severe colitis in the absence of LIGHT expression.
LIGHT是肿瘤坏死因子超家族的一员,它与两种受体,即光敏素B受体(LTBR)和疱疹病毒进入介体(HVEM)结合。转基因小鼠T细胞过度表达LIGHT导致结肠炎。然而,我们已经做出了令人惊讶的观察,即免疫缺陷Rag-/-小鼠中LIGHT表达的缺乏导致T细胞转移模型中结肠炎的增加。本申请中的实验旨在了解LIGHT表达在预防严重结肠炎中令人惊讶的抗炎作用。我们的初步数据表明,LIGHT通过结合LTBR在先天免疫系统中起作用。基于我们的数据和已发表的文献,我们提出巨噬细胞表达的LIGHT作用于这些细胞也表达的LTBR,以促进其凋亡,从而限制炎症。我们将结合免疫学和遗传学方法来检验我们的假设,并了解T淋巴细胞以外的细胞表达LIGHT在预防严重结肠炎中的意外作用。在目标1中,我们将表征LIGHT缺陷的Rag-/-受体小鼠中严重结肠炎的免疫发病机制。我们还将分析LIGHT表达减少对仅涉及先天免疫细胞的结肠炎模型的影响,我们将确定LIGHT的缺乏是否会影响某些细胞类型的凋亡,这是LIGHT:LTBR相互作用的已知结果。在目标2中,我们将证实(或反驳)表明严重结肠炎的预防依赖于LTBR表达的初步数据。在目标3中,我们将确定是否需要可溶性LIGHT,因为它在刀豆球蛋白A诱导的肝损伤中。目标4中的实验将确定必须表达LIGHT及其受体以预防严重疾病的关键细胞类型。最后,目标5中的实验将把小鼠模型的发现与患者研究联系起来。我们将研究影响IBD患者结肠炎发病机制的TNFSF 14(LIGHT)基因多态性,以确定这些多态性是否与LIGHT表达水平或LIGHT结合其受体的能力相关。因此,该项目中的实验应该会导致对LIGHT表达缺失情况下严重结肠炎潜在机制的深入了解。

项目成果

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MITCHELL KRONENBERG其他文献

MITCHELL KRONENBERG的其他文献

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{{ truncateString('MITCHELL KRONENBERG', 18)}}的其他基金

Host nutrients permit immune evasion of NKT cell anti-bacterial responses
宿主营养物质允许免疫逃避 NKT 细胞抗菌反应
  • 批准号:
    10312774
  • 财政年份:
    2018
  • 资助金额:
    $ 27.41万
  • 项目类别:
Host nutrients permit immune evasion of NKT cell anti-bacterial responses
宿主营养物质允许免疫逃避 NKT 细胞抗菌反应
  • 批准号:
    10089228
  • 财政年份:
    2018
  • 资助金额:
    $ 27.41万
  • 项目类别:
HVEM: A TNF family receptor that influences mucosal immunity and the microbiome
HVEM:影响粘膜免疫和微生物组的 TNF 家族受体
  • 批准号:
    9294945
  • 财政年份:
    2016
  • 资助金额:
    $ 27.41万
  • 项目类别:
The role of natural killer T cells in the innate response to lung infection
自然杀伤 T 细胞在肺部感染先天反应中的作用
  • 批准号:
    8632820
  • 财政年份:
    2014
  • 资助金额:
    $ 27.41万
  • 项目类别:
Research Resources: Epigenomic and Transcriptomic Profiles of Human Immune Cells
研究资源:人类免疫细胞的表观基因组和转录组图谱
  • 批准号:
    9112842
  • 财政年份:
    2014
  • 资助金额:
    $ 27.41万
  • 项目类别:
Research Resources: Epigenomic and Transcriptomic Profiles of Human Immune Cells
研究资源:人类免疫细胞的表观基因组和转录组图谱
  • 批准号:
    8895831
  • 财政年份:
    2014
  • 资助金额:
    $ 27.41万
  • 项目类别:
Research Resources: Epigenomic and Transcriptomic Profiles of Human Immune Cells
研究资源:人类免疫细胞的表观基因组和转录组图谱
  • 批准号:
    8740928
  • 财政年份:
    2014
  • 资助金额:
    $ 27.41万
  • 项目类别:
The role of natural killer T cells in the innate response to lung infection
自然杀伤 T 细胞在肺部感染先天反应中的作用
  • 批准号:
    8862370
  • 财政年份:
    2014
  • 资助金额:
    $ 27.41万
  • 项目类别:
The role of IL-10 in stabilizing natural regulatory T cells
IL-10 在稳定天然调节性 T 细胞中的作用
  • 批准号:
    8495226
  • 财政年份:
    2013
  • 资助金额:
    $ 27.41万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    8495232
  • 财政年份:
    2013
  • 资助金额:
    $ 27.41万
  • 项目类别:

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