Nogo receptor function at the synapse

Nogo 受体在突触的功能

基本信息

批准号：
8594705
负责人：
Katherine Therese Baldwin
金额：
$ 3.27万
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/8594705
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关键取决于神经元回路的正确组装、维护和活动依赖性修饰。尽管人们对胚胎神经系统发育过程中调节轴突生长和寻路的细胞外分子和信号通路了解很多，但对控制幼年和成年哺乳动物大脑和脊髓突触结构和功能的机制知之甚少。越来越多的证据表明，限制受损中枢神经系统中神经元萌芽的分子与限制健康（未受伤）中枢神经系统中神经元可塑性的分子存在密切重叠。我们实验室最近的研究表明，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递的信号传导机制尚未明确。这项研究将采用小鼠遗传学、原代神经细胞培养和基于生物化学的方法来定义 Nogo/NgR1 下游调节的信号通路，主要关注 PI3K/AKT/mTORC1 通路。在并行方法中，电生理记录和药物治疗的结合将用于检查先前观察结果的分子机制，即 NgR1 的缺失会减弱 CA3-CA1 突触的 LTD，并且 Nogo66 的应用会降低 CA1 神经元突触传递的 LTP 。 NgR1 种系和条件突变体的行为研究将评估 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，因此详细了解大脑结构和功能的调节方式在生物学和临床上都具有很大的意义。所提出的实验是对 Nogo 受体功能的系统分析，有望为神经系统生理学和病理学的关键方面提供见解。