The secreted form of Neuregulin-1 in schizophrenia

精神分裂症中 Neuregulin-1 的分泌形式

• 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
• 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

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。