Research Center for Molecular Pathogenesis of Schizophrenia

精神分裂症分子发病机制研究中心

• 批准号: 7516270
• 负责人: AKIRA SAWA
• 金额: $ 99.9万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-06-13 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7516270
• 关键词: Research; Center; Molecular; Pathogenesis; Schizophrenia

DESCRIPTION (provided by applicant): Schizophrenia is a disorder of neuronal connectivity, at least in part, with developmental origin. Functional disturbance of the cerebral cortex, especially the prefrontal cortex, has been reproducibly reported. Recent genetic studies have suggested that some of the genetic susceptibility factors may have a role in formation of synapses. These factors include Disrupted-ln-Schizophrenia (DISC1), neuronal nitric oxide synthase (nNOS), CAPON, NDEL1, and ErbB4. DISC1 interacts with several intracellular proteins, including Kalirin and other susceptibility factors for the disease, as an adaptor protein in the postsynaptic density. Thus, we will study a role for molecular pathway(s) involving DISC1 in synaptic spine formation in the developing cerebral cortex. In the first half of this project (Aims 1 and 2), we will use primary cortical neurons to elucidate molecular pathways of DISC1/ Kalirin-7 and DISC1/nNOS/NDEL1 for proper spine formation in pyramidal neurons, possibly by influencing Rho-like small G-proteins, especially Rac1. We hypothesize that DISC1 regulates access of Kalirin-7 and NDEL1 to Rac1 and related proteins, in response to the activation of the NMDA glutamate receptor, and regulates synaptic spine formation in a proper manner. In the second half of this project (Aim 3), we will test how disturbance of DISC1 and its interaction with Kalirin-7 and other synaptic proteins lead to morphological changes of the spines in vivo and result in behavioral alterations, which will be studied in collaboration with Core B. Key mediators studied in this project, including Kalirin-7 and Rac1, will be evaluated by genetic analysis in Core C. Taken together, we hope to clarify how convergence of two critical factors for schizophrenia, such as glutamate and DISC1, occurs at postsynaptic sites. We wish to elucidate mechanisms whereby this disease pathway, involving DISC1 and its interactors, leads to deficits in the synaptic spines in the pyramidal neurons of the frontal cortex and resultant behavioral abnormalities.

描述（由申请人提供）：精神分裂症是一种神经元连接障碍，至少部分是发育性的。大脑皮层的功能障碍，特别是前额叶皮层，已经有可重复的报道。最近的遗传学研究表明，一些遗传易感性因素可能在突触的形成中起作用。这些因素包括精神分裂症紊乱蛋白（DISC1）、神经元型一氧化氮合成酶（nNOS）、CAPON、NDEL1和ErbB4。DISC1与多种细胞内蛋白相互作用，包括Kalirin和其他疾病的易感因子，作为突触后密度的衔接蛋白。因此，我们将研究涉及DISC1的分子通路在发育中的大脑皮层突触棘形成中的作用。在这个项目的前半部分（目标1和目标2），我们将利用初级皮质神经元来阐明DISC1/ Kalirin-7和DISC1/nNOS/NDEL1在锥体神经元中正常脊柱形成的分子途径，可能是通过影响rho样小g蛋白，尤其是Rac1。我们假设DISC1调节Kalirin-7和NDEL1对Rac1及相关蛋白的通路，以响应NMDA谷氨酸受体的激活，并以适当的方式调节突触棘的形成。下半年的这个项目(目标3),我们将测试与Kalirin-7 DISC1的干扰及其交互和其他突触蛋白导致体内棘突的形态变化和导致行为改变,将研究与核心b关键介质研究合作在这个项目中,包括Kalirin-7和Rac1,将由遗传分析评估核心c .综上所述,我们希望澄清如何融合精神分裂的两个关键因素,如谷氨酸和DISC1，发生在突触后位点。我们希望阐明这种疾病通路的机制，包括DISC1及其相互作用因子，导致额叶皮质锥体神经元突触棘的缺陷和由此产生的行为异常。