Cell-Contact Mediated Mechanisms Assembling Synapses

细胞接触介导的突触组装机制

• 批准号: 9230361
• 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/9230361
• 关键词: Acute; Address; Alzheimer' s Disease; Amino Acids; Antibody Binding Sites; Anxiety; Autistic Disorder; Autoantibodies; 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; Pathologic; 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 Receptors; Synaptic plasticity; TYRP1 gene; Testing; Work; addiction; density; developmental disease; drug of abuse; experimental study; improved; in vivo; insight; painful neuropathy; protein B; public health relevance; receptor function; repaired; synaptic function; synaptogenesis; tool

DESCRIPTION (provided by applicant): 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.

描述(申请人提供)：此外，焦虑、神经性疼痛和阿尔茨海默病都被证明有一些重要的共同特征，如突触数量的变化和缺陷对NMDAR的功能或定位的调节。值得注意的是，在发育过程中，在成熟的大脑中，在这些不同的疾病中，EphB和ePhin-B蛋白似乎是控制这些事件的重要候选基因。然而，即使在正常情况下，我们对ePhin-B和EphB控制事件的机制的了解也是初步的。因此，我们将集中在两个问题上(1)EphB受体如何调节NMDAR在突触的定位和功能，以及(2)神经元如何控制它们接收的突触的数量。为了回答这些问题，我们提出了三个具体的目标：1.确定EphB2中的一个特定结构域是否必要且充分地控制EphB-NMDAR的相互作用。2.确定是否需要NR1中的特定结构域来控制EphB-NMDAR相互作用。3.确定依从性调节突触密度的分子机制我们的实验结果将为控制和指定大脑内突触连接的形成和功能的机制提供基本见解。此外，鉴于EphB/EphinB可以介导突触和结构可塑性，它们的表达受药物滥用的调节，并且Ephbs对NMDAR功能的调节与阿片成瘾有关，我们的研究将促进对药物诱导的病理的理解，并可能对人类健康产生广泛的影响。