NMDA Receptor Complex Dysfunction in Schizophrenia

精神分裂症中的 NMDA 受体复合体功能障碍

• 批准号: 7884418
• 负责人: Matthew L MacDonald
• 金额: $ 3.53万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7884418
• 关键词: Acute Erythroblastic Leukemia; Affect; Amino Acids; Antipsychotic Agents; Area; Attention; Autopsy; Binding; Brain; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium/calmodulin-dependent protein kinase; Cell Culture Techniques; Cells; Chronic; Complex; Data; Disease; ErbB4 gene; Etiology; Fractionation; Functional disorder; Genes; Goals; Homologous Gene; Human; Laboratories; Lead; Light; Liquid Chromatography; Mass Spectrum Analysis; Membrane; Methodology; Methods; Molecular; Molecular Genetics; Mus; N-Methyl-D-Aspartate Receptors; N-Methylaspartate; NR1 gene; Neuregulin 1; Neurotransmitters; Pathology; Pathway interactions; Patients; Phospholipase C; Phosphorylation; Phosphorylation Site; Pilot Projects; Population; Post-Translational Protein Processing; Prefrontal Cortex; Protein Kinase C; Proteins; Proteomics; Protocols documentation; Receptor Signaling; Reporting; Research; Research Project Grants; Risk; Role; Schizophrenia; Signal Pathway; Signal Transduction; Site; Stable Isotope Labeling; Susceptibility Gene; Testing; Tissues; Training; Viral Oncogene; aspartate receptor; base; brain tissue; calmodulin-dependent protein kinase II; career; career development; citrate carrier; density; drug discovery; experience; frontal lobe; mind control; multiple reaction monitoring; novel; protein complex; protein protein interaction; receptor; receptor binding; receptor function; research study; statistics; synthetic peptide

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.

描述（由申请人提供）：精神分裂症是一种慢性和衰弱的精神疾病，影响世界上1%的人口。基于药理学和分子遗传学研究，n -甲基- d -天冬氨酸受体功能障碍与该病的病理生理有关。最近，我们首次报道了n -甲基- d -天冬氨酸受体在精神分裂症患者死后脑组织中的受体功能下降的证据。n -甲基- d -天冬氨酸受体的受体功能受受体蛋白复合物中高度调控和复杂的蛋白质相互作用的支配。该研究的主要目标是描述精神分裂症患者死后脑组织中n -甲基- d -天冬氨酸受体复合物的蛋白质组成变化（目的1）。n -甲基- d -天冬氨酸受体复合物将免疫沉淀从人类精神分裂症患者和匹配的对照前额叶皮层分离的突触后密度部分。受体复合物的组成将通过靶向质谱法进行定性和定量评估。蛋白相互作用的失调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磷酸化状态的改变。要验证这一假设，需要对死后组织进行磷光组学分析。作为该项目的第二个目标，我们将开发和建立一种方法，通过质谱结合死后脑组织刺激范式来量化目标磷酸化，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，但申请人的经验和培训将有助于确定他在精神病理学磷光分析领域的职业发展轨迹。这个项目的成功完成将揭示蛋白质相互作用和N-甲基- d -天冬氨酸受体磷酸化的改变范围。这些数据将提供有关精神分裂症风险基因对疾病病理影响的机制信息，并为药物发现提供新的平台。相关性：神经递质因其在精神疾病（如精神分裂症）中的作用而受到广泛关注。该项目的目标是研究细胞中负责解释这些神经递质信号的机制，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了解这种疾病，并为药物发现打开新的大门。