Neuregulin 1-erbB signaling in schizophrenia

精神分裂症中的神经调节蛋白 1-erbB 信号传导

• 批准号: 7292681
• 负责人: Chang-Gyu Hahn
• 金额: $ 30.78万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-28 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7292681
• 关键词: Address; Anterior; Attenuated; Autopsy; Binding; Brain; Brain region; Co-Immunoprecipitations; Complex; Coupling; Cyclic AMP-Dependent Protein Kinases; Employee Strikes; Epidermal Growth Factor Receptor; ErbB4 gene; Figs - dietary; Functional disorder; Genetic; Hippocampus (Brain); Human; Immunoblotting; Inositol; Ligands; MAPK1 gene; Measures; Mediating; Modeling; Molecular Genetics; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NMDA receptor A1; NRG2 gene; NRG3 gene; Neuregulin 1; Neurobiology; Nitric Oxide Synthase Type I; Pathway interactions; Patients; Phospholipase; Phosphotransferases; Prefrontal Cortex; Proteins; Receptor Signaling; Relative (related person); Research Personnel; Rodent; Role; Schizophrenia; Signal Transduction; Specificity; Testing; Tissues; Tyrosine Phosphorylation; attenuation; brain tissue; density; design; human NRG3 protein; inhibitor/antagonist; interest; neurodevelopment; novel; postsynaptic; postsynaptic density protein; presynaptic density protein 95; programs; protein expression; protein protein interaction; receptor; receptor function; response; src-Family Kinases; upstream kinase

DESCRIPTION (provided by applicant): Recent molecular genetics studies implicate neuregulin 1 (NRG1) and its receptor, erbB, in the pathophysiology of schizophrenia. Among NRG 1 receptors, erbB4 is of particular interest because of its crucial roles in neurodevelopment and in modulation of N-methyl-D-aspartate (NMDA) receptor signaling. We have recently examined the expression and transduction of the NRG1- erbB4 mechanism in the postmortem brains of schizophrenia and control subjects. Using a novel postmortem tissue stimulation approach, we found striking alterations of NRG1- erbB4 signaling in the prefrental cortex of schizophrenia subjects. First, NRG1-induced erbB4 activation, measured by tyrosine phosphorylation of erbB4 and its association with PSD-95, was dramatically enhanced, while the expression levels of NRG1 or erbB4 were not altered. Second, the association of erbB4 with PSD-95 and NMDAR as well as PSD-95's coupling with NMDAR were also significantly altered in schizophrenia. Third, NRG1 stimulation attenuates NMDAR activation in the human prefrontal cortex as shown in rodents. NMDAR activation, measured by tyrosine phosphorylation of the receptors, was significantly attenuated in schizophrenia subjects, which we believe to be the first direct demonstration of NMDAR hypofunction in the brains of patients. Finally, when the brain tissues were co-stimulated with NMDA and NRG1, NRG1 induced NMDA attenuation was even greater in schizophrenia subjects, suggesting that the dyregulated NRG1 -erbB4 signaling in schizophrenia may contribute to NMDAR hypofunction. Our central hypothesis is that altered erbB4 signaling in schizophrenia is associated with altered protein -protein interactions in the PSD, including NMDAR complexes. The aims of this proposal are designed to test a model in which altered erbB4 - postsynaptic density (PSD) protein association in schizophrenia leads to enhanced erbB4 signaling, which in turn results in NMDAR hypofunction. By doing so, we will be able to explore whether dysregulated protein - protein interactions in the PSD is a pathophysiologic mechanism for schizophrenia. Aim 1 will first assess whether hyperactive erbB4 signaling is brain region- or ligand-specific in schizophrenia. Aim 2 will specifically address protein protein interactions among erbB4 and other PSD proteins. Aim 3, will further characterize the impact of erbB4 dysregulation on NMDAR signaling and explore possible mechanisms.

描述（由申请人提供）：最近的分子遗传学研究表明神经调节蛋白 1 (NRG1) 及其受体 erbB 与精神分裂症的病理生理学有关。在 NRG 1 受体中，erbB4 特别令人感兴趣，因为它在神经发育和 N-甲基-D-天冬氨酸 (NMDA) 受体信号传导调节中发挥着至关重要的作用。我们最近检查了精神分裂症和对照受试者死后大脑中 NRG1-erbB4 机制的表达和转导。使用一种新颖的死后组织刺激方法，我们发现精神分裂症受试者的前额皮质中 NRG1-erbB4 信号发生显着改变。首先，通过 erbB4 酪氨酸磷酸化及其与 PSD-95 的关联来测量，NRG1 诱导的 erbB4 激活显着增强，而 NRG1 或 erbB4 的表达水平没有改变。其次，erbB4 与 PSD-95 和 NMDAR 的关联以及 PSD-95 与 NMDAR 的耦合在精神分裂症中也显着改变。第三，NRG1 刺激会减弱人类前额皮质中 NMDAR 的激活，如啮齿动物中所示。通过受体酪氨酸磷酸化测量的 NMDAR 激活在精神分裂症受试者中显着减弱，我们认为这是患者大脑中 NMDAR 功能减退的首次直接证明。最后，当脑组织与 NMDA 和 NRG1 共同刺激时，精神分裂症受试者中 NRG1 诱导的 NMDA 衰减甚至更大，这表明精神分裂症中 NRG1 -erbB4 信号传导失调可能导致 NMDAR 功能减退。我们的中心假设是，精神分裂症中 erbB4 信号传导的改变与 PSD 中蛋白质-蛋白质相互作用的改变有关，包括 NMDAR 复合物。该提案的目的是测试一个模型，在该模型中，精神分裂症中 erbB4 - 突触后密度 (PSD) 蛋白关联的改变会导致 erbB4 信号传导增强，进而导致 NMDAR 功能减退。通过这样做，我们将能够探索 PSD 中蛋白质-蛋白质相互作用失调是否是精神分裂症的病理生理机制。目标 1 将首先评估精神分裂症中过度活跃的 erbB4 信号传导是否具有脑区域特异性或配体特异性。目标 2 将专门解决 erbB4 和其他 PSD 蛋白之间的蛋白质相互作用。目标 3 将进一步表征 erbB4 失调对 NMDAR 信号传导的影响并探索可能的机制。