NMDA Receptor Complex Dysfunction in Schizophrenia

描述(申请人提供)：精神分裂症是一种慢性和衰弱的精神疾病，影响着世界1%的人口。根据药理学和分子遗传学的研究，N-甲基-D-天冬氨酸受体功能低下与该病的病理生理学有关。最近，我们首次报道了精神分裂症患者死后脑组织N-甲基-D-天冬氨酸受体功能下降的证据。N-甲基-D-天冬氨酸受体的功能由受体蛋白复合体中高度调控和复杂的蛋白质相互作用所控制。拟议研究的主要目标是描绘精神分裂症受试者死后人脑组织中N-甲基-D-天冬氨酸受体复合体的改变的蛋白质组成(目标1)。N-甲基-D-天冬氨酸受体复合体将从人类精神分裂症患者和匹配对照的前额叶皮质的突触后密度组分中免疫沉淀。受体复合体的组成将通过靶向质谱法进行定性和定量的评估。蛋白质相互作用的异常调节可能是由于突触后密度蛋白-95和N-甲基-D-天冬氨酸受体-NR2A的磷酸化状态改变所致。检验这一假设需要对死后组织进行光学分析。作为该项目的次要目标，我们将开发和建立结合死后脑组织刺激范例的质谱学方法来量化目标磷酸化，然后将其应用于一小部分死后脑组织(目标2)。虽然Aim 2项目仍将作为试点研究，但申请者的经验和培训将有助于确定他在精神病理学光学分析领域的职业发展轨迹。该项目的成功完成将揭示N-甲基-D-天冬氨酸受体上改变的蛋白质相互作用和磷酸化的范围。这些数据将提供有关精神分裂症风险基因对疾病病理学影响的机械信息，并为药物发现提供新的平台。相关性：神经递质因其在精神分裂症等精神疾病中的作用而备受关注。该项目的目标是研究负责解释这些神经递质信号的细胞中的机制，并确定它们是否在精神分裂症患者的大脑中功能失调。这项研究将有助于我们对这种疾病的了解，并为药物发现打开新的大门。

DESCRIPTION (provided by applicant): Schizophrenia is a chronic and debilitating psychiatric illness affecting 1% of the world's population. N-methyl-D-aspartic acid receptor hypofunction has been implicated for the pathophysiology of the illness based on pharmacologic and molecular genetics studies. Recently, we have reported the first evidence that N-methyl-D-aspartic acid receptor receptor function was decreased in postmortem brain tissues of patients with schizophrenia. N-methyl-D-aspartic acid receptor receptor function is governed by highly regulated and intricate protein protein interactions in the receptor protein complexes. The primary goal of the proposed research is to delineate altered protein composition of the N-methyl-D-aspartic acid receptor complex in human postmortem brain tissue from schizophrenic subjects (Aim 1). N-methyl-D- aspartic acid receptor complexes will be immunoprecipitated from post-synaptic density fractions isolated from human schizophrenic and matched control pre-frontal cortexes. Receptor complex composition will be assessed qualitative and quantitatively by targeted mass spectroscopy method. Dysregulations in protein interactions could be due to altered the phosphorylation states of post-synaptic density protein -95 and N- methyl-D-aspartic acid receptor- NR2A. Testing this hypothesis will require phosphotomic analysis of postmortem tissues. As the secondary goal of this project, we will develop and establish the method to quantify target phosphorylations by mass spectroscopy in conjunction with the postmortem brain tissue stimulation paradigm, which will then be applied to a small set of postmortem brain tissues (Aim 2). While Aim 2 projects will remain as a pilot study, the applicant's experience and training will help define the trajectory of his career in the field of phosphotomic analysis for psychiatric pathology. Successful completion of this project will shed light on the extend of altered protein interactions and phosphorylation at the N- methyl-D-aspartic acid receptor. This data will provide mechanistic information as to the impact of schizophrenia risk genes on disease pathology and inform new platforms for drug discovery. Relevance: Neurotransmitters receive a lot of attention for their role in psychiatric illnesses, such as schizophrenia. The goal of this project is to investigate the machinery in the cell responsible for interpreting these neurotransmitter signals and determine if they are dysfunctional in the brains of schizophrenic patients. This research will aid our understanding of the disease and open new doors for drug discovery.