Cell-Contact Mediated Mechanisms Assembling Synapses

细胞接触介导的突触组装机制

• 批准号: 8638586
• 负责人: Matthew B Dalva
• 金额: $ 31万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8638586
• 关键词: Acute; Address; Alzheimer' s Disease; Amino Acids; Antibody Binding Sites; Anxiety; Autistic Disorder; Automobile Driving; Binding; Biochemistry; Biological Neural Networks; Brain; Candidate Disease Gene; Catatonia; Cells; Complement; Data; Defect; Development; Disease; Electrophysiology (science); Ephrin B Receptor; Ephrin-B2; Ephrin-B3; Ephrins; Epilepsy; Event; Excitatory Synapse; Extracellular Domain; Glutamate Receptor; Health; Human; Immunohistochemistry; In Vitro; Laboratories; Ligands; Link; MAP Kinase Gene; Mediating; Membrane Proteins; Molecular; Morphology; Mutation; N-Methyl-D-Aspartate Receptors; NR1 gene; Nervous System Physiology; Neurons; Neurotransmitter Receptor; Opiate Addiction; Pathology; Pathway interactions; Pharmaceutical Preparations; Play; Postsynaptic Membrane; Process; Proteins; Psychotic Disorders; Receptor Protein-Tyrosine Kinases; Regulation; Reporting; Research; Role; Signal Transduction; Site; Slice; Specific qualifier value; Structure; Synapses; Synaptic plasticity; Testing; Work; addiction; density; developmental disease; drug of abuse; improved; in vivo; inhibiting antibody; insight; interest; painful neuropathy; protein B; public health relevance; receptor function; repaired; research study; synaptic function; synaptogenesis; tool

Abstract Addition, anxiety, neuropathic pain and Alzheimer's disease have each been shown to share some important common features such as changes in synapse number and defectives regulation of the function or localization of the NMDAR. Remarkably EphB and ephrin-B proteins appear to be important candidate genes in the control of these events during development, in the mature brain, and in these diverse diseases. Yet, our understanding of the mechanisms by which ephrin-Bs and EphB control the events even under normal conditions is rudimentary. Therefore we will focus on two issues (1) how the EphB receptor regulates NMDAR localization and function at synapses and (2) how neurons control the number of synapses they receive. To answer these questions we propose three specific aims: 1. Determine whether a specific domain in EphB2 is necessary and sufficient to control the EphB-NMDAR interaction. 2. Determine whether a specific domain in NR1 is necessary to control the EphB-NMDAR interaction. 3. Determine the molecular mechanisms mediating ephrin-B3 dependent control of synapse density Results from our experiments will provide fundamental insights into mechanisms that control and specify the formation and function of synaptic connections within the brain. In addition, given that EphB/ephrinB can mediate synaptic and structural plasticity, that their expression is regulated by drugs of abuse, and EphBs regulation of NMDAR function has been linked to opiate addiction, our studies will advance understanding of drug-induced pathology and will likely have broad impact on human health.

摘要 此外，焦虑、神经性疼痛和阿尔茨海默病都被证明是 有一些重要的共同特征，如突触数量的变化， NMDAR的功能或定位的缺陷调节。关于EphB 和肝配蛋白-B蛋白似乎是控制这些的重要候选基因 在发育过程中的事件，在成熟的大脑中，以及在这些不同的疾病中。但我们的 了解肝配蛋白B和EphB控制事件的机制， 在正常情况下是基本的。因此，我们将重点关注两个问题：（1）如何 EphB受体调节NMDAR在突触的定位和功能，以及（2）如何 神经元控制它们接收的突触数量。为了回答这些问题， 提出三个具体目标：1.确定EphB 2中的特定结构域是否是 必需且足以控制EphB-NMDAR相互作用。2.确定 NR 1中的特定结构域是否是控制EphB-NMDAR所必需的 互动3.确定介导ephrin-B3的分子机制 突触密度依赖性控制 我们的实验结果将为我们提供有关机制的基本见解， 控制和指定大脑内突触连接的形成和功能。在 此外，考虑到EphB/ephrinB可以介导突触和结构可塑性， 它们的表达受药物滥用和EphBs对NMDAR的调节的调节 功能与阿片类药物成瘾有关，我们的研究将促进对 药物引起的病理学，并可能对人类健康产生广泛影响。