Nogo receptor function at the synapse

Nogo 受体在突触的功能

基本信息

批准号：
8672217
负责人：
Katherine Therese Baldwin
金额：
$ 3.32万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-08-01 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8672217
关键词：
AMPA Receptors Address Adolescent Adult Affect Affinity Amino Acids Attenuated Autistic Disorder Behavioral Biochemical Biochemistry Brain Brain Diseases C-terminal Cell Culture Techniques Data Dendritic Spines Development Embryonic Nervous System Exhibits Family member Genetic Growth Growth Factor Hippocampus (Brain)Human Knowledge Laboratories Learning Light Long-Term Depression Long-Term Potentiation Maintenance Memory Mental Retardation Messenger RNA Modification Molecular Mus Mutant Strains Mice Myelin Natural regeneration Nervous System Physiology Neuronal Plasticity Neurons Outcome PI3K/AKT Paper Pathology Pathway interactions Pharmacological Treatment Physiological Process Prosencephalon Protein Biosynthesis Proteins Proteomics RTN4 gene Regulation Research Role Schizophrenia Seminal Signal Pathway Signal Transduction Spinal Cord Structure Synapses Synaptic Transmission Synaptic plasticity Testing Translations Two-Dimensional Gel Electrophoresis Work axon growth axonal pathfinding axonal sprouting base central nervous system injury extracellular genetic manipulation growth inhibitory proteins human FRAP1 protein inhibitor/antagonist injured insight interest loss of function mutant nervous system development nervous system disorder novel therapeutics oligodendrocyte-myelin glycoprotein overexpression public health relevance receptor receptor function research study synaptic function synaptogenesis

项目摘要

DESCRIPTION (provided by applicant): Proper nervous system function critically depends on the proper assembly, maintenance, and activity- dependent modification of neuronal circuits. Although a great deal is known about extracellular molecules and signaling pathways that regulate axonal growth and pathfinding during embryonic nervous system development, comparatively little is known about the mechanisms that control synaptic structure and function in the juvenile and adult mammalian brain and spinal cord. Mounting evidence suggests that there is a close overlap of molecular players that limit neuronal sprouting in the injured CNS, and molecules that restrict neuronal plasticity in the healthy (uninjured) CNS. Recent studies from our lab revealed that the growth inhibitory proteins Nogo/RTN4 and oligodendrocyte myelin glycoprotein (OMgp) suppress activity-dependent synaptic plasticity in an NgR1-dependent manner. The signaling mechanisms employed by NgR1 to regulate synaptic structure and synaptic transmission have not yet been defined. This research will pursue mouse genetic, primary neuronal cell culture, and biochemistry-based approaches to define the signaling pathways regulated downstream of Nogo/NgR1, with a primary focus on the PI3K/AKT/mTORC1 pathway. In a parallel approach, a combination of electrophysiological recordings and pharmacological treatments will be used to examine the molecular mechanisms underlying the previous observations that loss of NgR1 attenuates LTD at CA3-CA1 synapses, and that application of Nogo66 decreases LTP of synaptic transmission in CA1 neurons. Behavioral studies in NgR1 germline and conditional mutants will assess the importance of NgR1 signaling in learning and memory. Because changes in neuronal structure and synaptic function often correlate with brain disease, a detailed understanding of how brain structure and function is regulated is of great interest, both biologically and clinically. Experiments proposed are a systematic analysis of Nogo receptor function, and are expected to provide insights into key aspects of nervous system physiology and pathology.

描述（由申请人提供）：正确的神经系统功能严重取决于神经元电路的适当组装，维护和依赖于活动的修饰。尽管对细胞外分子和信号通路有很多了解，这些细胞外分子和信号通路在胚胎神经系统发育过程中调节轴突生长和探路，但对于控制少年和成人哺乳动物脑和脊髓中的突触结构和功能的机制，知之甚少。越来越多的证据表明，分子玩家限制了受伤的中枢神经系统中神经元发芽的紧密重叠，并且分子限制了健康（未受伤的）CNS中神经元可塑性的分子。我们实验室的最新研究表明，生长抑制蛋白NoGo/RTN4和少突胶质细胞髓磷脂糖蛋白（OMGP）以NGR1依赖性方式抑制活性依赖性突触可塑性。 NGR1用于调节突触结构和突触传播的信号传导机制尚未定义。这项研究将追求小鼠遗传，原发性神经元细胞培养和基于生物化学的方法来定义调节Nogo/Ngr1下游的信号通路，主要关注PI3K/AKT/MTORC1途径。在平行方法中，将使用电生理记录和药理学治疗的结合来检查先前观察结果的基础机制，即NGR1的损失减弱了Ca3-CA1突触处的LTD，而NOGO66的应用降低了CA1神经元突触传播LTP的LTP。 NGR1种系和条件突变体中的行为研究将评估NGR1信号在学习和记忆中的重要性。由于神经元结构和突触功能的变化通常与脑部疾病相关，因此在生物学和临床上，对大脑结构和功能的调节方式的详细理解都引起了人们的极大兴趣。提出的实验是对Nogo受体功能的系统分析，并有望提供有关神经系统生理和病理学关键方面的见解。