Trophic Interactions of Nerve and Muscle

描述（由申请人提供）：烟碱乙酰胆碱受体（nAChR）家族成员的分子生物学和生物化学研究，包括本项目过去支持的研究，发现了这些原型配体门控离子通道的几个有趣和意外的特性。这一点在对一种特定的nAChR亚型（α 7 nAChR）的研究中表现得最为明显。例如，我们现在知道，编码单个α 7亚基的mRNA的表达能够允许全功能乙酰胆碱门控通道的表达，该通道令人惊讶地以与NMDA受体相当的渗透性流动钙。此外，我们知道α 7受体在海马体中表达，海马体是记忆形成的重要脑区，α 7受体调节该脑区的神经元功能。最后，在上一个项目期间，我们在alpha 7受体方面有了两个令人惊讶的发现。我们发现海马α 7受体激活促分裂原活化蛋白激酶（MAPK）级联，这是一种用于调节基因表达和触发海马长期细胞变化的原型信号转导级联。我们和其他几个研究小组沿着还发现，阿尔茨海默病的可能致病因子--淀粉样β肽是α 7受体的高亲和力配体。后两项发现为我们在下一个项目期间提出的研究提供了基础。在下一阶段的研究中，我们将提出以下三个问题：1。在海马神经元中，α 7/MAPK通路是否调节BDNF基因作为靶点，以及染色质结构的调节是否参与了这一过程？2. A-β肽与海马Schaffer/侧支突触的α 7 nAChR相互作用的长期生理后果是什么？3.使用基因工程小鼠模型在体内研究的A-β/α 7 nAChR相互作用的行为后果是什么？这些实验的动机是我们希望了解的生理作用和机制的α 7乙酰胆碱受体在中枢神经系统中的作用，并了解其潜在的贡献神经系统疾病。

DESCRIPTION (provided by applicant): Molecular biological and biochemical studies of the members of the nicotinic acetylcholine receptor (nAChR) Family, including those studies supported in the past by this Project, have allowed the discovery of several interesting and unanticipated properties of these prototypical ligand-gated ion channels. Nowhere is this more apparent than in studies of one specific nAChR subtype: the alpha7 nAChR. For example, we now know that the expression of the mRNA encoding a single alpha7 subunit is capable of allowing expression of a fully functional acetylcholine-gated channel, which surprisingly fluxes calcium with a permeability on par with the NMDA receptor. Moreover, we know that the alpha7 receptor is expressed in the hippocampus, a brain region important for memory formation, and that the alpha7 receptor modulates neuronal function in this brain region. Finally, in the last Project Period, we made two discoveries concerning alpha7 receptors that also were surprising. We discovered that hippocampal alpha7 receptors activate the Mitogen-Activated Protein Kinase (MAPK) cascade, the prototypical signal transduction cascade for regulating gene expression and triggering long-term cellular change in the hippocampus. We, along with several other groups, also discovered that the likely causative agent for Alzheimer's Disease, the amyloid beta peptide, is a high-affinity ligand for alpha7 receptors. These latter two discoveries provide the basis for the studies we are proposing for the next Project Period. In the next phase of our studies we will ask the following three questions: 1. Does the alpha7/MAPK pathway regulate the BDNF gene as a target in hippocampal neurons, and is regulation of chromatin structure involved in this process? 2. What are the long-term physiologic consequences of the A-beta peptide interaction with the alpha7 nAChR at hippocampal Schaffer/collateral synapses? 3. What are the behavioral consequences of the A-beta/alpha7 nAChR interaction, studied in vivo using genetically engineered mouse models? These experiments are motivated by our desire to understand the physiologic roles and mechanisms of action of the alpha7 nAChR in the CNS, and to understand its potential contribution to neurological disorders.