Cell-Contact Mediated Mechanisms Assembling Synapses

描述（由申请人提供）：此外，焦虑、神经性疼痛和阿尔茨海默病已被证明具有一些重要的共同特征，如突触数量的变化和NMDAR功能或定位的调节缺陷。值得注意的是，EphB和ephrin-B蛋白似乎是重要的候选基因，在发育过程中控制这些事件，在成熟的大脑中，以及在这些不同的疾病中。然而，即使在正常情况下，我们对ephrin- b和EphB控制这些事件的机制的理解也是初步的。因此，我们将重点关注两个问题：(1)EphB受体如何调节NMDAR在突触中的定位和功能；(2)神经元如何控制它们接收的突触数量。为了回答这些问题，我们提出三个具体目标：确定EphB2中的特定结构域是否对控制EphB-NMDAR相互作用是必要和充分的。2. 确定NR1中的特定结构域是否控制EphB-NMDAR相互作用。3. 确定介导ephrin-B3依赖性突触密度控制的分子机制我们的实验结果将为控制和指定脑内突触连接的形成和功能的机制提供基本的见解。此外，考虑到EphB/ephrinB可以介导突触和结构可塑性，它们的表达受滥用药物的调节，以及EphB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病理的理解，并可能对人类健康产生广泛的影响。

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.