Generation and Characterization of GAD67-ErbB4 Transgenic Mice

GAD67-ErbB4 转基因小鼠的产生和表征

基本信息

  • 批准号:
    7618793
  • 负责人:
  • 金额:
    $ 16.17万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2008
  • 资助国家:
    美国
  • 起止时间:
    2008-05-01 至 2010-04-30
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia is a complex psychiatric disorder that is extremely difficult to model in rodents because of structural difference between human and mouse brains, lack of clear pathological hallmarks of the disorder, and inability of mice to demonstrate human psychiatric phenotypes such as delusion, hallucination, or depression. This argues for models to create a piecemeal of different components in schizophrenia with discrete endpoints in behavioral, physiological, and molecular analyses. Such an approach has proved useful in generating and analyzing schizophrenic rodent models. Both neuregulin-1 (NRG1) and its receptor ErbB4 are susceptibility genes of schizophrenia. Recent evidence suggests a gain-of-function of NRG1 signaling in the prefrontal cortex (PFC) in schizophrenic patients. Increased expression of type I NRG1 and CYT-1/JMa ErbB4 have been reported in the PFC of patients with schizophrenia. Moreover, NRG1 signaling was found to be enhanced in the same area of postmortem brains from schizophrenic patients. Despite of the clinic evidence for NRG1/ErbB4 gain-of-function in schizophrenia, there has not been such a rodent model. This appears to be a bottle neck for further in vivo studies of cellular, molecular as well as behavioral deficits and pathological mechanisms of NRG1 and ErbB4 mutations. In preliminary studies, we demonstrated that NRG1, via ErbB4, regulates activity-dependent GABA release in the PFC. Therefore, we propose to generate and characterize GAD67-ErbB4 transgenic mice overexpressing human CYT-1/JMa ErbB4. The R21 Phase has three Specific Aims: 1) Generation of GAD67-ErbB4 transgenic mice; 2) Determine whether NRG1 signaling and induced activity-dependent GABA release are increased in GAD67-ErbB4 transgenic mice; and 3) Determine whether NRG1 regulation of GABA transmission is increased in GAD67-ErbB4 transgenic mice. The R33 Phase has two Specific Aims: 1) Determine whether NRG1 suppression of pyramidal neuron activity is up-regulated in GAD67-ErbB4 mice and 2) Determine whether GAD67-ErbB4 transgenic mice can model working memory deficits, positive and negative symptoms and attentional deficits in schizophrenia. It is our hope that the gain-of- function model of ErbB4 signaling will provide critical insight into pathogenic mechanisms and pathways of NRG1 and ErbB4, two important susceptibility genes. The transgenic mice might be useful for testing chemicals and biological reagents that could facilitate the development of novel therapeutic interventions of schizophrenia. Moreover, successful generation and characterization of GAD67-ErbB4 transgenic mice will offer a proof of principle for other NRG1 gain-of-function models in different regions of the brain. This is a proposal to generate GAD67-ErbB4 transgenic mice over-expressing human CYT-1/JMa ErbB4 to model neurotransmission and behavioral deficits in schizophrenia. The gain-of-function model of ErbB4 signaling will provide critical insight into pathogenic mechanisms and pathways of NRG1 and ErbB4, two important susceptibility genes of schizophrenia.
描述(由申请人提供):精神分裂症是一种复杂的精神疾病,由于人和小鼠大脑之间的结构差异,缺乏明确的疾病病理学特征,以及小鼠无法证明人类精神病表型,如妄想、幻觉或抑郁,因此极难在啮齿动物中建模。这就要求模型在精神分裂症中创建一个不同组成部分的碎片,在行为,生理和分子分析中具有离散的端点。这种方法已被证明在产生和分析精神分裂症啮齿动物模型中是有用的。神经调节蛋白1(NRG 1)及其受体ErbB 4是精神分裂症的易感基因。最近的证据表明,在精神分裂症患者的前额叶皮层(PFC)的NRG 1信号的功能获得。据报道,精神分裂症患者PFC中I型NRG 1和CYT-1/JMa ErbB 4的表达增加。此外,NRG 1信号被发现在精神分裂症患者死后大脑的同一区域增强。尽管有临床证据表明精神分裂症中存在NRG 1/ErbB 4功能获得性,但尚未有这样的啮齿动物模型。这似乎是一个瓶颈,进一步在体内研究的细胞,分子以及行为缺陷和病理机制的NRG 1和ErbB 4突变。在初步研究中,我们证明,NRG 1,通过ErbB 4,调节活性依赖性GABA释放PFC。因此,我们建议产生和表征GAD 67-ErbB 4转基因小鼠过表达人CYT-1/JMa ErbB 4。R21阶段有三个特定目的:1)GAD 67-ErbB 4转基因小鼠的产生; 2)确定GAD 67-ErbB 4转基因小鼠中NRG 1信号传导和诱导的活性依赖性GABA释放是否增加; 3)确定GAD 67-ErbB 4转基因小鼠中NRG 1对GABA传递的调节是否增加。R33阶段有两个特定目的:1)确定锥体神经元活动的NRG 1抑制是否在GAD 67-ErbB 4小鼠中上调,2)确定GAD 67-ErbB 4转基因小鼠是否可以模拟精神分裂症的工作记忆缺陷、阳性和阴性症状以及注意力缺陷。我们希望ErbB 4信号转导的功能获得性模型将为NRG 1和ErbB 4这两个重要易感基因的致病机制和途径提供重要的见解。转基因小鼠可能有助于测试化学和生物试剂,可以促进精神分裂症新的治疗干预措施的发展。此外,GAD 67-ErbB 4转基因小鼠的成功产生和表征将为大脑不同区域的其他NRG 1功能获得模型提供原理证明。这是一种产生过表达人CYT-1/JMa ErbB 4的GAD 67-ErbB 4转基因小鼠以模拟精神分裂症中的神经传递和行为缺陷的提议。ErbB 4信号通路的功能获得性模型将为精神分裂症两个重要易感基因NRG 1和ErbB 4的致病机制和通路提供重要的见解。

项目成果

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Lin Mei其他文献

Lin Mei的其他文献

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{{ truncateString('Lin Mei', 18)}}的其他基金

NRG1-ErbB4 regulation of synaptic plasticity and behavior
NRG1-ErbB4 对突触可塑性和行为的调节
  • 批准号:
    9452123
  • 财政年份:
    2018
  • 资助金额:
    $ 16.17万
  • 项目类别:
Agrin signaling in maintaining neuromuscular junction in aging
集聚蛋白信号传导在衰老过程中维持神经肌肉接头
  • 批准号:
    9145617
  • 财政年份:
    2015
  • 资助金额:
    $ 16.17万
  • 项目类别:
Characterization of Agrin/LRP4 Antibody-Positive Myasthenia Gravis
Agrin/LRP4 抗体阳性重症肌无力的特征
  • 批准号:
    8977954
  • 财政年份:
    2015
  • 资助金额:
    $ 16.17万
  • 项目类别:
Agrin signaling in maintaining neuromuscular junction in aging
集聚蛋白信号传导在衰老过程中维持神经肌肉接头
  • 批准号:
    9276547
  • 财政年份:
    2015
  • 资助金额:
    $ 16.17万
  • 项目类别:
Mechanisms of Erbin regulation of remyelination
Erbin调控髓鞘再生的机制
  • 批准号:
    9275337
  • 财政年份:
    2013
  • 资助金额:
    $ 16.17万
  • 项目类别:
Neuromuscular junction regeneration
神经肌肉接头再生
  • 批准号:
    10047696
  • 财政年份:
    2013
  • 资助金额:
    $ 16.17万
  • 项目类别:
Neuromuscular junction regeneration
神经肌肉接头再生
  • 批准号:
    10296649
  • 财政年份:
    2013
  • 资助金额:
    $ 16.17万
  • 项目类别:
LRP4 signaling in neuromuscular junction formation
LRP4 信号在神经肌肉接头形成中的作用
  • 批准号:
    9604664
  • 财政年份:
    2013
  • 资助金额:
    $ 16.17万
  • 项目类别:
Neuromuscular junction regeneration
神经肌肉接头再生
  • 批准号:
    10647628
  • 财政年份:
    2013
  • 资助金额:
    $ 16.17万
  • 项目类别:
Mechanisms of Erbin regulation of remyelination
Erbin调控髓鞘再生的机制
  • 批准号:
    8442521
  • 财政年份:
    2013
  • 资助金额:
    $ 16.17万
  • 项目类别:

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  • 批准号:
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临床记录中缩写词的实时消歧
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    8305149
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