Trophic Interactions of Nerve and Muscle

描述(由申请人提供)：对烟碱型乙酰胆碱受体(NAChR)家族成员的分子生物学和生化研究，包括过去由该项目支持的那些研究，使这些典型的配体门控离子通道的一些有趣和意想不到的特性得以发现。在对一种特定的nAChR亚型的研究中，这一点最为明显：α7 nAChR。例如，我们现在知道，编码单个α7亚基的mRNA的表达能够允许一个全功能的乙酰胆碱门控通道的表达，该通道令人惊讶地以与NMDA受体相当的通透性来输送钙。此外，我们知道Alpha7受体在海马区表达，这是一个对记忆形成至关重要的大脑区域，并且Alpha7受体调节该脑区的神经功能。最后，在最后一个项目期间，我们有了两个关于α7受体的发现，这也是令人惊讶的。我们发现，海马α7受体激活了丝裂原活化蛋白激酶(MAPK)级联，这是调节基因表达和触发海马区长期细胞变化的典型信号转导级联。我们和其他几个小组还发现，阿尔茨海默病的可能病因--淀粉样β蛋白多肽--是一种Alpha7受体的高亲和力配体。后两项发现为我们为下一个项目期提出的研究提供了基础。在我们下一阶段的研究中，我们将提出以下三个问题：1.α7/MAPK通路是否调控海马神经元中的BDNF基因，以及染色质结构的调节是否参与了这一过程？2.A-β肽与α7 nAChR在海马Schaffer/侧枝突触相互作用的长期生理后果是什么？3.用基因工程小鼠模型在体内研究A-β/α7 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α7 nAChR在中枢神经系统中的生理作用和作用机制，并了解其对神经疾病的潜在贡献。

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.