Cell cell adhesion among embryonic cells

描述(申请人提供)：自从我们发现神经细胞以来 黏附分子，N-CAM，在20多年前，结合已经变得明显 细胞黏附分子(CAM)不仅介导细胞与细胞之间的相互作用，而且 也会产生影响胚胎发育和成人生理的信号。在……里面 在这些已提出的研究中，我们主要关注N-CAM在调节关键分子中的作用 神经系统中的细胞功能。我们的第一个目标是 阐明N-CAM结合到细胞膜上和细胞膜下的事件 细胞表面诱导细胞内信号。N-CAM的诱导能力 转录因子核因子-KB作为范例，但研究将是 扩展到其他N-CAM介导的事件。重组蛋白对应于 N-CAM的各种胞外部分将用于检查结合事件， 并将使用N-CAM细胞质区域的定点突变来 分析细胞内事件。在第二个目标中，N-CAM诱导的能力 神经干细胞与神经干细胞结合向神经元分化的研究 异嗜性(非N-CAM)受体将从机制的角度进行研究 刺激，涉及的受体，和诱导的神经元类型 N-CAM结合。多价重组蛋白将被用来诱导 并与我们的N-CAM基因敲除小鼠的细胞联合应用 分离异嗜性受体。在第三个目标中，我们将考察 N-CAM在突触长时程增强(LTP)诱导中的作用 潜在的记忆和学习。在这些研究中，突触动力学和 将比较两种N-CAM基因敲除小鼠的形态，其中一种是 海马区LTP组和非LTP组。我们为此开发的一种新方法 将使用识别活跃突触的群体。已定义的机制 通过这些研究，应该成为其他CAM活动的范例。 他们还应该对CAM如何调控基因表达产生新的见解， 为神经干细胞分化提供新的试剂 临床应用，并扩大我们对基本机制的认识 记忆和学习是基础。

DESCRIPTION (provided by applicant): Since our discovery of the neural cell adhesion molecule, N-CAM, over 20 years ago, it has become clear that binding by cell adhesion molecules (CAMs) not only mediates cell-cell interactions, but also induces signals that affect embryonic development and adult physiology. In these proposed studies, we focus on the role of N-CAM in regulating critical cellular functions in the nervous system. Our first aim is designed to elucidate the events at and under the cell membrane by which N-CAM binding to the cell surface induces intracellular signals. The ability of N-CAM to induce the transcription factor NF-KB serves as the paradigm, but the studies will be extended to other N-CAM-mediated events. Recombinant proteins corresponding to various extracellular portions of N-CAM will be used to examine binding events, and site-directed mutagenesis of the N-CAM cytoplasmic region will be used to analyze intracellular events. In the second aim, the ability of N-CAM to induce the differentiation of neural stem cells into neurons by binding to heterophilic (non-N-CAM) receptors will be examined in terms of the mechanism of stimulation, the receptors involved, and the types of neurons induced by N-CAM binding. Multivalent recombinant proteins will be used to induce the response and be applied in conjunction with cells from our N-CAM knock-out mice to isolate heterophilic receptors. In the third aim, we will examine the role of N-CAM in inducing long term potentiation (LTP) of synapses, a key process underlying memory and learning. For these studies, synaptic dynamics and morphology will be compared in two strains of N-CAM knock-out mice, one with hippocampal LTP and one without LTP. A new method we have developed for identifying populations of active synapses will be used. The mechanisms defined by these studies should serve as exemplars for the activities of other CAMs. They should also yield new insights into how CAMs regulate gene expression, provide novel reagents for differentiating neural stem cells for potential clinical use, and expand our knowledge of the fundamental mechanisms that underlie memory and learning.