NEURONAL ACTIVITY REGULATED PENTRAXIN AND GLUTAMATE REC

描述（来自申请人摘要的逐字记录）：我们的研究重点是 蛋白质合成依赖性突触的分子机制 可塑性。特别是，我们正在研究立即早期基因（IEG） 称为Narp，其基于其响应于 突触活性（Tsui等，1996年）。Narp（神经活性调节） 正五聚体蛋白）是一种分泌的、自我多聚化的蛋白质， 神经元在最近的研究中，我们发现，Narp是选择性富集在 轴-树兴奋性突触。此外，Narp诱导AMPA类型的簇 外源细胞表面的谷氨酸受体，并选择性地 与脑中的AMPA受体发生免疫共沉淀。纳普显示了广泛的 在突触发生之前和之后与AMPA受体共定位，以及 Narp的瞬时上调导致兴奋性神经元数目增加， 突触基于这些观察，我们假设Narp调节 AMPA受体的突触聚集，并在兴奋性 突触发生目标1-3中描述的研究将定义 Narp膜表面自聚簇结构与功能关系 因为它与AMPA受体有关。常规突变分析和 遗传方法将用于确定相互作用的关键位点， 这些分子。基于这些信息，肽和抗体拮抗剂 将开发扰动集群活动的Narp和测试其作用 在自然的突触发生中。目的4-5将检查细胞生物学特性 在大脑神经元中。研究将测试假设，纳普是 针对特定的兴奋性突触，它可以修改他们的 兴奋性突触的形态和功能特性。由于纳普是 作为一个IEG，我们的研究将为分子和细胞生物学提供新的见解。 活动依赖性突触可塑性的机制。

DESCRIPTION (Verbatim from the Applicant's Abstract): Our research focuses on molecular mechanisms that underlie protein synthesis-dependent synaptic plasticity. In particular, we are examining an immediate early gene (IEG) termed Narp that was identified based on its rapid up-regulation in response to synaptic activity (Tsui et al., 1996). Narp (Neuronal activity-regulated Pentraxin) is a secreted, self-multimerizing protein that is expressed by neurons. In recent studies, we find that Narp is selectively enriched at axo-dendritic excitatory synapses. Moreover, Narp induces clusters of AMPA-type glutamate receptors on the surface of heterologous cells, and selectively co-immunoprecipitates with AMPA receptors from brain. Narp shows extensive co-localization with AMPA receptors, both before and after synaptogenesis, and transient up-regulation of Narp results in an increased number of excitatory synapses. Based on these observations, we hypothesize that Narp modulates synaptic clustering of AMPA receptors and plays a role in excitatory synaptogenesis. Studies described in Aims 1-3 will define the structure-function relationships for Narp membrane surface self-clustering and for its association with AMPA receptors. Conventional mutation analyses and genetic approaches will be used to define the critical sites of interaction for these molecules. Based on this information, peptide and antibody antagonists will be developed to perturb the clustering activity of Narp and test its role in natural synaptogenesis. Aims 4-5 will examine the cell biological properties of Narp in brain neurons. Studies will test the hypotheses that Narp is targeted to specific excitatory synapses and that it can modify their morphological and functional properties of excitatory synapses. Since Narp is an IEG, our research will provide new insights into the molecular and cellular mechanisms of activity dependent synaptic plasticity.