The secreted form of Neuregulin-1 in schizophrenia

精神分裂症中 Neuregulin-1 的分泌形式

基本信息

  • 批准号:
    8825231
  • 负责人:
  • 金额:
    $ 23.78万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2014
  • 资助国家:
    美国
  • 起止时间:
    2014-09-15 至 2016-08-31
  • 项目状态:
    已结题

项目摘要

DESCRIPTION (provided by applicant): Schizophrenia is a devastating neuropsychiatric disorder, affecting about 1.1% of the population over the age of 18. Human and mouse genetic studies have identified several schizophrenia susceptibility genes. Among them, neuregulin-1 (Nrg1), a pleiotropic signaling molecule, is confirmed as a risk gene for schizophrenia (Stefansson et al., 2002;Hall et al., 2006;Law et al., 2006). How functional changes in Nrg1 signaling lead to schizophrenia is an important research topic. Proteolytic cleavage of Nrg1 is required to release a functional fragment that will interact with its cognate receptors of the ErbB family to exert cell-cell signaling (Falls, 2003;Mei and Xiong, 2008). In our studies of BACE1, which was initially discovered as the -secretase for cleaving amyloid precursor protein to release A (Vassar et al., 1999;Yan et al., 1999;Hussain et al., 1999;Sinha et al., 1999;Lin et al., 2000), we have shown that BACE1 cleaves transmembrane Nrg1 to release a secreted EGF-domain- containing N-terminal fragment and to exert a signaling function (Hu et al., 2008;Fleck et al., 2013). Mice with deficiency in BACE1 exhibit altered Nrg1 signaling function and develop schizophrenia-like phenotypes (Savonenko et al., 2008). One intriguing question is whether enhancing Nrg1 activity in BACE1-null mice will ameliorate behaviors. Related to this question, we have recently generated a mouse model which expressed BACE1-cleaved Nrg1 N-terminal fragment (termed as Nrg1-ntf ) under the control of tetracycline (Tet) responsible element (Tet-Off promoter). We found that overexpression of Nrg1-ntf in transgenic mice (Tg- N1 /T mice) enhances Nrg1 signaling activity, as its downstream signaling molecules Akt and Erk are activated. However, contrary to our expectations, our functional study shows that Tg-N1 /T mice develop schizophrenia- like behaviors, which can be reversed if transgene expression is switched off. Results from our lab and others imply that abnormally hypo- or hyper-functional Nrg1 can lead to schizophrenia. Since the dys-regulated expression of schizophrenia susceptibility genes may affect normal brain development and lead to the gradual appearance of different symptoms at different ages (Piper et al., 2012;Powell, 2010;Rapoport et al., 2005), we aim to test our hypothesis that increased Nrg1 activity during early development, but not during adulthood, contributes to subsequent schizophrenia-like behaviors in the adult. To test our hypothesis in this study, we propose two specific aims. Aim 1: To determine whether increased Nrg1 activity in the adult has an impact on schizophrenia-like behaviors. Aim 2: To explore molecular mechanisms associated with schizophrenia-like behaviors in N1 /T transgenic mice.
描述(申请人提供):精神分裂症是一种毁灭性的神经精神疾病,影响约1.1%的18岁以上的人口。人类和小鼠的遗传研究已经确定了几个精神分裂症易感基因。其中,神经调节蛋白-1(Nrg 1),一种多效性信号分子,被证实为精神分裂症的风险基因(Stefansson et al.,2002;Hall等人,2006;Law等人,2006年)。Nrg 1信号通路的功能变化如何导致精神分裂症是一个重要的研究课题。需要Nrg 1的蛋白水解切割以释放将与ErbB的同源受体相互作用的功能片段 家族发挥细胞-细胞信号传导(福尔斯,2003;Mei和Xiong,2008)。在我们对BACE 1的研究中,最初发现BACE 1是用于切割淀粉样前体蛋白以释放A的β-分泌酶(Vassar等人,1999年;Yan等人,1999年;侯赛因等人,1999年;Sinha等人,1999;Lin等人, 2000),我们已经表明BACE 1切割跨膜Nrg 1以释放分泌的含有EGF结构域的N-末端片段并发挥信号传导功能(Hu et al.,2008;Fleck等人,2013年)。具有BACE 1缺陷的小鼠表现出改变的Nrg 1信号传导功能并发展出精神分裂症样表型(Savonenko等人,2008年)。一个有趣的问题是,增强BACE 1基因敲除小鼠的Nrg 1活性是否会改善行为。与此相关,我们最近建立了一种小鼠模型,该模型在四环素(泰特)责任元件(Tet-Off启动子)的控制下表达BACE 1切割的Nrg 1 N-末端片段(称为Nrg 1-ntf)。我们发现Nrg 1-ntf在转基因小鼠(Tg-N1/T小鼠)中的过表达增强了Nrg 1信号传导活性,因为其下游信号分子Akt和Erk被激活。然而,与我们的预期相反,我们的功能研究表明,Tg-N1 /T小鼠发展出精神分裂症样行为,如果关闭转基因表达,这种行为可以逆转。我们实验室和其他实验室的结果表明,异常低或高功能的Nrg 1可能导致精神分裂症。由于精神分裂症易感基因的表达失调可能会影响正常的大脑发育,并导致不同年龄段逐渐出现不同的症状(Piper等人,2012;Powell,2010;Rapoport等人,2005),我们的目标是测试我们的假设,即在早期发育过程中增加Nrg 1活性,但不是在成年期,有助于成年后的精神分裂症样行为。为了验证我们的假设,在这项研究中,我们提出了两个具体目标。目的1:确定成人Nrg 1活性增加是否对精神分裂症样行为有影响。目的2:探讨N1 /T转基因小鼠精神分裂症样行为的分子机制。

项目成果

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RIQIANG YAN其他文献

RIQIANG YAN的其他文献

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{{ truncateString('RIQIANG YAN', 18)}}的其他基金

Role of the CX3CL1 C-terminus in reversing age-dependent Alzheimers neurodegeneration
CX3CL1 C 末端在逆转年龄依赖性阿尔茨海默病神经变性中的作用
  • 批准号:
    10594845
  • 财政年份:
    2022
  • 资助金额:
    $ 23.78万
  • 项目类别:
Role of the CX3CL1 C-terminus in reversing age-dependent Alzheimers neurodegeneration
CX3CL1 C 末端在逆转年龄依赖性阿尔茨海默病神经变性中的作用
  • 批准号:
    9691661
  • 财政年份:
    2018
  • 资助金额:
    $ 23.78万
  • 项目类别:
Role of the CX3CL1 C-terminus in reversing age-dependent Alzheimers neurodegeneration
CX3CL1 C 末端在逆转年龄依赖性阿尔茨海默病神经变性中的作用
  • 批准号:
    9456462
  • 财政年份:
    2017
  • 资助金额:
    $ 23.78万
  • 项目类别:
Role of the CX3CL1 C-terminus in reversing age-dependent Alzheimers neurodegeneration
CX3CL1 C 末端在逆转年龄依赖性阿尔茨海默病神经变性中的作用
  • 批准号:
    10709060
  • 财政年份:
    2017
  • 资助金额:
    $ 23.78万
  • 项目类别:
The secreted form of Neuregulin-1 in schizophrenia
精神分裂症中 Neuregulin-1 的分泌形式
  • 批准号:
    8925147
  • 财政年份:
    2014
  • 资助金额:
    $ 23.78万
  • 项目类别:
Inhibition of BACE1 for benefiting Alzheimer's patients
抑制 BACE1 可使阿尔茨海默病患者受益
  • 批准号:
    8741927
  • 财政年份:
    2013
  • 资助金额:
    $ 23.78万
  • 项目类别:
Inhibition of BACE1 for benefiting Alzheimer's patients
抑制 BACE1 可使阿尔茨海默病患者受益
  • 批准号:
    9304940
  • 财政年份:
    2013
  • 资助金额:
    $ 23.78万
  • 项目类别:
Inhibition of BACE1 for benefiting Alzheimer's patients
抑制 BACE1 可使阿尔茨海默病患者受益
  • 批准号:
    8878977
  • 财政年份:
    2013
  • 资助金额:
    $ 23.78万
  • 项目类别:
Inhibition of BACE1 for benefiting Alzheimer's patients
抑制 BACE1 可使阿尔茨海默病患者受益
  • 批准号:
    9111767
  • 财政年份:
    2013
  • 资助金额:
    $ 23.78万
  • 项目类别:
Inhibition of BACE1 for benefiting Alzheimer's patients
抑制 BACE1 可使阿尔茨海默病患者受益
  • 批准号:
    8641971
  • 财政年份:
    2013
  • 资助金额:
    $ 23.78万
  • 项目类别:

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