Trophic Interactions of Nerve and Muscle

神经和肌肉的营养相互作用

• 批准号: 7913462
• 负责人: John David Sweatt
• 金额: $ 18.74万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-15 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7913462
• 关键词: Acetylcholine; Affinity; Alzheimer' s Disease; Amyloid beta-Protein; BDNF gene; Behavioral; Biochemical; Biological; Brain region; Chromatin Structure; Family; Gated Ion Channel; Gene Expression; Genetically Engineered Mouse; Hippocampus (Brain); Ligands; Memory; Mitogen-Activated Protein Kinases; Molecular; Muscle; N-Methyl-D-Aspartate Receptors; Nerve; Neurons; Nicotinic Receptors; Pathway interactions; Peptides; Permeability; Phase; Physiological; Process; Property; Regulation; Role; Signal Transduction; Synapses; alpha-bungarotoxin receptor; base; in vivo; interest; mRNA Expression; member; mouse model; nervous system disorder; receptor; release of sequestered calcium ion into cytoplasm; research study

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.

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，包括该项目过去支持的那些研究，允许发现这些原型配体的几种有趣且意外的特性。在研究一种特定的NACHR亚型：alpha7 nachr的研究中，没有什么比这更明显的了。例如，我们现在知道编码单个alpha7亚基的mRNA的表达能够允许表达功能齐全的乙酰胆碱门控通道，这令人惊讶地使钙具有与NMDA受体相当的渗透性。此外，我们知道α7受体在海马中表达，这是对记忆形成重要的大脑区域，并且α7受体在该大脑区域调节神经元功能。最后，在最后一个项目时期，我们对α7受体进行了两个发现，这也令人惊讶。我们发现海马α7受体激活了有丝分裂原激活的蛋白激酶（MAPK）级联反应，这是用于调节基因表达的原型信号转导级联级联，并触发海马的长期细胞变化。我们与其他几个组一起发现，阿尔茨海默氏病的可能致病剂，淀粉样蛋白β肽，是α7受体的高亲和力配体。这两个发现为我们在下一个项目时期提议的研究提供了基础。在我们的下一阶段，我们将提出以下三个问题：1。α7/MAPK途径是否调节BDNF基因为海马神经元中的靶标，并且在此过程中涉及的染色质结构的调节吗？ 2。在海马Schaffer/侧支突触上，A-Beta肽与α7NACHR的长期生理后果是什么？ 3。使用基因工程的小鼠模型在体内研究了A-BETA/Alpha7 NACHR相互作用的行为后果是什么？这些实验是出于我们渴望了解α7NACHR在中枢神经系统中的生理作用和作用机理的愿望，并了解其对神经系统疾病的潜在贡献。