Novel Transgenic Mouse Models to Analyze TRPM2 and ADP-Ribose Function

用于分析 TRPM2 和 ADP-核糖功能的新型转基因小鼠模型

基本信息

  • 批准号:
    8603848
  • 负责人:
  • 金额:
    $ 7.93万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2013
  • 资助国家:
    美国
  • 起止时间:
    2013-01-09 至 2015-12-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): The adequate level, localization, and temporal development of Ca2+-signals are crucial to an appropriate and effective immune response. The objective of this proposal is to generate novel transgenic mouse models to explore the role in innate immune functions of the novel Ca2+-mobilizing second messenger ADP-ribose (ADPR), and of its effector molecule, the ADPR-gated TRPM2 ion channel. Several metabolites of the cellular electron carrier NAD(P)+ are emerging as an unsuspected group of Ca2+-homeostasis regulators. Whereas cyclic ADPR and NAADP can both deplete intracellular Ca2+-stores, ADPR mediates Ca2+-entry into the cytosol by binding the gating domain of the TRPM2 ion channel. Conditions of oxidative stress as encountered in inflammatory environments are expected to lead to ADPR production as a consequence of the activation of NAD+- and DNA-depleting "rescue and repair" pathways. In support of this idea, TRPM2-mediated Ca2+-influx is triggered following external application of H2O2. The recent characterization of a TRPM2-deficient mouse model has shown that TRPM2 is essential for H2O2-mediated cytokine production in monocytes. Using a different TRPM2-/- mouse strain, we found that TRPM2 is required for host-defense against listeriosis, further supporting the finding that TRPM2 plays a crucial role in the immune system. Moreover, gene expression levels of TRPM2 appear to be differentially regulated in accordance to the maturation and activation status of specific immune cell subpopulations, implying that the ability to respond to ADPR-accumulation via TRPM2 is carefully orchestrated. We thus reason that forcing the expression of TRPM2 in cells that would not otherwise express it might result in developmental and functional aberrations, shedding some light on TRPM2/ADPR- mediated signaling. In order to understand how the manipulation of TRPM2 and ADPR levels might impact immune responses in vivo, we therefore propose to establish two novel mouse strains with targeted integration into the mouse genomic ROSA26 locus of the following constructs: 1) A Cre-inducible expression construct of the highly selective ADPR-hydolase NudT9 allowing to selectively reduce cytosolic ADPR-levels in mice. 2) A similar construct allowing for Cre-mediated expression of TRPM2. Once obtained, these strains will be crossed onto Cre-expressing mouse lines of choice, for example to obtain myeloid cell restricted expression of the transgenes. Preliminary studies will assess the cellular composition of immune relevant organs and the susceptibility of the transgenic stains to Lm infection. These studies will allow us to assess the potential of this type of approaches for immunomodulatory and therapeutic purposes.
描述(由申请人提供):Ca2+信号的适当水平、定位和时间发展对于适当且有效的免疫反应至关重要。本提案的目的是生成新型转基因小鼠模型,以探索新型 Ca2+ 动员第二信使 ADP-核糖 (ADPR) 及其效应分子(ADPR 门控 TRPM2 离子通道)在先天免疫功能中的作用。细胞电子载体 NAD(P)+ 的几种代谢物正在作为一组意想不到的 Ca2+ 稳态调节剂出现。虽然环状 ADPR 和 NAADP 都可以消耗细胞内 Ca2+ 储备,但 ADPR 通过结合 TRPM2 离子通道的门控结构域介导 Ca2+ 进入细胞质。由于 NAD+ 和 DNA 消耗“拯救和修复”途径的激活,炎症环境中遇到的氧化应激条件预计会导致 ADPR 产生。为了支持这一观点,外部应用 H2O2 后会触发 TRPM2 介导的 Ca2+ 内流。 TRPM2 缺陷小鼠模型的最新表征表明,TRPM2 对于单核细胞中 H2O2 介导的细胞因子产生至关重要。使用不同的TRPM2-/-小鼠品系,我们发现TRPM2是宿主防御李斯特菌病所必需的,进一步支持了TRPM2在免疫系统中发挥关键作用的发现。此外,TRPM2的基因表达水平似乎根据特定免疫细胞亚群的成熟和激活状态进行差异性调节,这意味着通过TRPM2响应ADPR积累的能力是精心策划的。因此,我们推断,强迫原本不表达 TRPM2 的细胞表达 TRPM2 可能会导致发育和功能异常,从而为 TRPM2/ADPR 介导的信号传导提供一些线索。为了了解 TRPM2 和 ADPR 水平的操纵如何影响体内免疫反应,因此,我们建议建立两种新型小鼠品系,将以下构建体靶向整合到小鼠基因组 ROSA26 位点中:1)高选择性 ADPR 水解酶 NudT9 的 Cre 诱导表达构建体,允许选择性降低小鼠中的胞质 ADPR 水平。 2) 类似的构建体允许 Cre 介导的 TRPM2 表达。一旦获得,这些品系将与选择的表达 Cre 的小鼠品系杂交,例如以获得转基因的骨髓细胞限制表达。初步研究将评估免疫相关器官的细胞组成以及转基因染色剂对 Lm 感染的敏感性。这些研究将使我们能够评估此类方法用于免疫调节和治疗目的的潜力。

项目成果

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ANNE-LAURE PERRAUD其他文献

ANNE-LAURE PERRAUD的其他文献

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{{ truncateString('ANNE-LAURE PERRAUD', 18)}}的其他基金

The TRPM2 Ion Channel in Hepatic Innate Immunity
肝脏先天免疫中的 TRPM2 离子通道
  • 批准号:
    8882242
  • 财政年份:
    2014
  • 资助金额:
    $ 7.93万
  • 项目类别:
The TRPM2 Ion Channel in Hepatic Innate Immunity
肝脏先天免疫中的 TRPM2 离子通道
  • 批准号:
    8702878
  • 财政年份:
    2014
  • 资助金额:
    $ 7.93万
  • 项目类别:
Novel Transgenic Mouse Models to Analyze TRPM2 and ADP-Ribose Function
用于分析 TRPM2 和 ADP-核糖功能的新型转基因小鼠模型
  • 批准号:
    8493695
  • 财政年份:
    2013
  • 资助金额:
    $ 7.93万
  • 项目类别:
Function of L-Type Ca2+ Channels in B-Lymphocytes
B 淋巴细胞中 L 型 Ca2 通道的功能
  • 批准号:
    7575751
  • 财政年份:
    2008
  • 资助金额:
    $ 7.93万
  • 项目类别:
Function of L-Type Ca2+ Channels in B-Lymphocytes
B 淋巴细胞中 L 型 Ca2 通道的功能
  • 批准号:
    7450983
  • 财政年份:
    2008
  • 资助金额:
    $ 7.93万
  • 项目类别:
Cellular regulation of magnesium homeostasis
镁稳态的细胞调节
  • 批准号:
    6884661
  • 财政年份:
    2004
  • 资助金额:
    $ 7.93万
  • 项目类别:
Cellular regulation of magnesium homeostasis
镁稳态的细胞调节
  • 批准号:
    7413402
  • 财政年份:
    2004
  • 资助金额:
    $ 7.93万
  • 项目类别:
Cellular regulation of magnesium homeostasis
镁稳态的细胞调节
  • 批准号:
    7228548
  • 财政年份:
    2004
  • 资助金额:
    $ 7.93万
  • 项目类别:
Cellular regulation of magnesium homeostasis
镁稳态的细胞调节
  • 批准号:
    7057799
  • 财政年份:
    2004
  • 资助金额:
    $ 7.93万
  • 项目类别:
Cellular regulation of magnesium homeostasis
镁稳态的细胞调节
  • 批准号:
    6774303
  • 财政年份:
    2004
  • 资助金额:
    $ 7.93万
  • 项目类别:

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