Synaptic targeting and regulation of NMDAR subunits

NMDAR 亚基的突触靶向和调节

• 批准号: 8647007
• 负责人: John Alan Gray
• 金额: $ 18.08万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-05-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8647007
• 关键词: Address; Alzheimer' s Disease; Binding; Biochemical; Brain; C-terminal; Chronic; Clinical; Cognitive; Complex; Data; Development; Disease; Dissection; Electrophysiology (science); Endocytosis; Excision; Functional disorder; Genetic; Goals; Gray unit of radiation dose; Hippocampus (Brain); Image; Individual; Institution; Ischemic Stroke; K-Series Research Career Programs; Knockout Mice; Laboratory Research; Lead; Ligands; Literature; Mediating; Mental Depression; Mentors; Modeling; Molecular; Molecular and Cellular Biology; N-Methyl-D-Aspartate Receptors; Nature; Neurocognitive; Neurons; Neurosciences; Pathway interactions; Pharmacology; Phosphorylation; Phosphotyrosine; Physiology; Plastics; Play; Postdoctoral Fellow; Process; Property; Prosencephalon; Proteins; Proteomics; Psychiatrist; Recombinants; Regulation; Research; Resistance; Role; Schizophrenia; Scientist; Slice; Structure; Surface; Symptoms; Synapses; Synaptic plasticity; TFAP2A gene; Tail; Therapeutic; Training; Tyrosine; Tyrosine Phosphorylation; addiction; density; frontier; improved; innovation; insight; neurodevelopment; neuropsychiatry; novel; novel therapeutics; programs; protein protein interaction; public health relevance; receptor; receptor function; src-Family Kinases; synaptic function; theories; trafficking

DESCRIPTION (provided by applicant): The overall goal of this research program is to better understand the molecular mechanisms by which N-methyl-D-aspartate receptors (NMDARs) are regulated to modulate synapse development and synaptic plasticity, and how these processes might be disrupted in complex neuropsychiatric disorders such as schizophrenia. The applicant for this K08 Mentored Clinical Scientist Research Career Development Award, Dr. John Gray, is a psychiatrist and a postdoctoral fellow with Dr. Roger Nicoll at UCSF. Dr. Gray's long-term research goals are to lead an independent research laboratory in psychiatric neuroscience at an academic institution combining cellular, molecular, electrophysiological, and genetic approaches to study synapse function with the goal of understanding how disruptions of the normal mechanisms of synapse development might underlie the pathophysiology of major neuropsychiatric disorders. Though etiological mechanisms underlying schizophrenia remain largely unknown, a convergence of pharmacologic and genetic data implicates a dysregulation of NMDAR function. NMDARs play critical roles in neurodevelopment and synaptic plasticity and subtle changes in NMDAR functioning can have wide-ranging developmental and cognitive effects. Most forebrain NMDARs contain two GluN1 and two GluN2A or GluN2B subunits, with receptor trafficking and functional properties largely dictated by the GluN2 subunit composition. Until recently the dogma in the field was that NMDARs were relatively immobile fixed structures, though it is now apparent that there is a remarkable plasticity of synaptic NMDARs. Indeed, the expression, trafficking, synaptic localization and functioning of different NMDARs subtypes are under dynamic cellular control, though the mechanisms are poorly understood. In this research plan, the roles of GluN2 subunit C-terminal tails in NMDAR synaptic targeting, trafficking, and regulation will be systematically investigated using an innovative molecular replacement approach in which native NMDARs are removed and replaced by recombinant NMDAR subunits in individual neurons. By combining his training in molecular and cellular biology, receptor pharmacology, and synaptic electrophysiology, Dr. Gray will pursue additional training in biochemical and proteomic analysis to address the following specific aims: 1) to determine the role of GluN2B-S1480 phosphorylation in NMDAR trafficking; 2) to determine the mechanism of GluN2A targeting to synapses; and 3) to determine the role of tyrosine phosphorylation in NMDAR trafficking and regulation. Successful completion of this proposal will identify novel trafficking mechanisms, new targeting motifs and new proteins important in NMDAR regulation and synaptic development and plasticity and will open new frontiers for the development of disease-modifying therapeutic approaches for schizophrenia and other neuropsychiatric disorders.

描述（由申请人提供）：本研究项目的总体目标是更好地了解N-甲基-D-天冬氨酸受体（NMDAR）调节突触发育和突触可塑性的分子机制，以及这些过程在复杂的神经精神疾病（如精神分裂症）中可能如何被破坏。K 08指导临床科学家研究职业发展奖的申请人John Gray博士是一名精神病学家，也是UCSF Roger Nicoll博士的博士后研究员。格雷博士的长期研究目标是在一个学术机构领导一个独立的精神神经科学研究实验室，结合细胞，分子，电生理和遗传方法来研究突触功能，以了解突触发育的正常机制的破坏如何成为主要神经精神疾病的病理生理学基础。虽然精神分裂症的病因机制在很大程度上仍然未知，药理学和遗传学数据的融合暗示了NMDAR功能失调。NMDAR在神经发育和突触可塑性中起关键作用，并且NMDAR功能的细微变化可具有广泛的发育和认知影响。大多数前脑NMDAR含有两个GluN 1和两个GluN 2A或GluN 2B亚基，受体运输和功能特性主要由GluN 2亚基组成决定。直到最近，该领域的教条是NMDAR是相对固定的固定结构，尽管现在很明显，突触NMDAR具有显着的可塑性。事实上，不同NMDAR亚型的表达、运输、突触定位和功能都处于动态细胞控制之下，尽管其机制知之甚少。在这项研究计划中，GluN 2亚基C-末端尾在NMDAR突触靶向，运输和调节中的作用将使用创新的分子替代方法进行系统研究，其中天然NMDAR被去除并被单个神经元中的重组NMDAR亚基取代。通过结合他在分子和细胞生物学，受体药理学和突触电生理学方面的培训，Gray博士将继续进行生物化学和蛋白质组学分析方面的额外培训，以解决以下具体目标：1）确定GluN 2B-S1480磷酸化在NMDAR运输中的作用; 2）确定GluN 2A靶向突触的机制;和3）确定酪氨酸磷酸化在NMDAR运输和调节中的作用。该提案的成功完成将确定新的贩运机制，新的靶向基序和新的蛋白质在NMDAR调节和突触发育和可塑性中的重要性，并将为精神分裂症和其他神经精神疾病的疾病修饰治疗方法的发展开辟新的前沿。