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：
RIQIANG YAN
金额：
$ 23.78万
依托单位：
CLEVELAND CLINIC LERNER COM-CWRU
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

来源：
https://reporter.nih.gov/project-details/8825231
关键词：
ARHGEF5 gene Address Adolescence Adult Affect Age Amyloid beta-Protein Precursor Antipsychotic Agents Appearance Back Behavior Behavioral Behavioral Genetics Bioinformatics Biological Brain C-terminal Cleaved cell Clinical Defect Development Diagnosis Disease Doxycycline EGF gene Early Diagnosis Early Intervention Elements ErbB Receptor Family Protein Exhibits Genes Genetic Human Knockout Mice Lead Length Mediating Modeling Molecular Molecular Profiling Mus Mutate N-terminal Neuregulin 1 Outcome Pathogenesis Patients Peptide Hydrolases Pharmaceutical Preparations Phenotype Population Proteomics Quality of life Research Role Sampling Schizophrenia Signal Transduction Signaling Molecule Site Specific qualifier value Staging Susceptibility Gene Symptoms Synaptic plasticity Testing Tetracycline Control Tetracyclines Transgenes Transgenic Mice Validation age group base beta-site APP cleaving enzyme 1 comparative early adolescence emerging adult expectation falls in vivo intercellular communication mouse model myelination neuropsychiatry novel overexpression promoter public health relevance remyelination research study risk variant secretase stem transgene expression young adult

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（由申请人提供）：精神分裂症是一种毁灭性的神经精神疾病，影响了18岁以上约1.1％的人口。人类和小鼠遗传研究已经确定了几个精神分裂症易感基因。其中，神经蛋白1（NRG1）（一种多效信号分子）被证实为精神分裂症的风险基因（Stefansson等，2002; Hall等，2006; Law等，2006）。 NRG1信号传导的功能变化如何导致精神分裂症是一个重要的研究主题。需要NRG1的蛋白水解裂解才能释放一种功能性片段，该功能片段将与其ERBB的同源受体相互作用施加细胞细胞信号传导（Falls，2003; Mei and Xiong，2008）。在我们对BACE1的研究中，最初被发现是裂解淀粉样蛋白前体蛋白以释放A的分泌酶（Vassar等，1999; Yan等，1999; Hussain et al。 2000年），我们已经表明，Bace1裂解跨膜NRG1释放一个分泌的含有N末端片段的分泌的EGF域，并发挥信号传导函数（Hu等，2008; Fleck等，2013）。 Bace1缺乏的小鼠表现出改变的NRG1信号传导功能并发展出精神分裂症样的表型（Savonenko等，2008）。一个有趣的问题是，增强BACE1-NULL小鼠中NRG1活性是否会改善行为。与这个问题相关，我们最近生成了一个小鼠模型，该模型表达了在四环素（TET）负责元素（TET-OFF启动子）的控制下，表达了BACE1旋转的NRG1 N末端片段（称为NRG1-NTF）。我们发现，随着其下游信号分子Akt和ERK的激活，转基因小鼠（TG-N1 /T小鼠）中NRG1-NTF的过表达增强了NRG1信号传导活性。但是，与我们的期望相反，我们的功能性研究表明，TG-N1 /T小鼠会发展精神分裂症类似的行为，如果转基因表达被关闭，可以逆转。我们实验室和其他实验室的结果表明，异常的功能低下或高功能的NRG1可能导致精神分裂症。 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.为了在这项研究中检验我们的假设，我们提出了两个具体目标。目的1：确定成年人的NRG1活性是否增加对精神分裂症样行为有影响。目的2：探索与N1 /T转基因小鼠中与精神分裂症样行为相关的分子机制。