Synaptic Remodeling and Thyroid Hormones

突触重塑和甲状腺激素

• 批准号: 7059806
• 负责人: LEGIER V ROJAS
• 金额: $ 15.24万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-01-01 至 2009-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7059806
• 关键词: acetylcholine; cholinergic receptors; confocal scanning microscopy; electrophysiology; hormone regulation /control mechanism; hyperthyroidism; hypothyroidism; minority institution research support; neural transmission; neuromuscular junction; neurotransmitter transport; phenotype; synapses; thyroid hormones

The primary goal of this project is to elucidate the molecular mechanisms by which thyroid hormones regulate the neuromuscular transmission at the vertebrate neuromuscular junction. The proposed studies will address a series of fundamental questions regarding the action of Thyroid hormones (THs) in the mammalian neuromuscular junction (NMJ). The pre- and post-synaptic effects of THs on the mammalian endplate will be characterized. The following 3 aims are proposed: Aim 1. The working hypothesis is that THs control the basal miniature endplate current (MEPC) frequency. In sub-aim 1a, we propose to characterize the acute action of THs on the spontaneous neurotransmitter release from the presynaptic element of the mammalian NMJ. Sub-aim1b, have been designed to characterize the molecular mechanism involved in the non-transcriptional action of THs. Aim 2. We propose that the modification of THs levels cause changes in the spontaneous animal locomotion, which can be explained by peripheral THs' action. We will study how alterations in THs levels produce phenotype modifications (i.e., in spontaneous locomotion, rearing, etc.) in short-term and long-term hypo- and hyperthyroid mice. Furthermore, we will correlate these phenotype modifications with structural variation in the NMJ elements evaluated using confocal microscopy. Aim 3. We hypothesize that THs could interact directly with the postsvnaptic acetvlcholine receptor (AChR) channel. We plan to directly assess this interaction evaluating the activity of the AChR channel in muscle fibers dissociate from Control, hypo- and hyper-thyroid mice using outside-out patches and fast perfusion methodology. These studies extend our previous work to a second phase, in which a variety of approaches developed during the last two years will be applied to define physiological aspects of the effects of THs in mammalian NMJ. Millions of Americans (near 2% of the population) are affected by thyroid dysfunction. There is a disparity between our current understandings of the basic mechanism underlying THs action in the nervous system and the beneficial effects that THs are known to provide.

该项目的主要目标是阐明甲状腺激素的分子机制 调节脊椎动物神经肌肉连接处的神经肌肉传播。拟议的研究将 解决有关甲状腺激素（THS）在 哺乳动物神经肌肉连接（NMJ）。 THS对哺乳动物的前后突触后作用 端板将被描述。提出了以下3个目标： AIM 1。工作假设是控制基底微型终板电流（MEPC）频率。 在Sub-Aim 1a中，我们建议表征THS对自发神经递质的急性作用 从哺乳动物NMJ的突触前元素释放。 sub-aim1b，已设计为 表征参与THS非转录作用的分子机制。 AIM 2。我们提出，THS水平的修饰会导致自发动物的变化 运动可以通过外围Ths的动作来解释。我们将研究如何在THS级别的变化 短期和长期产生表型修饰（即自发运动，饲养等） 甲状腺功能低下的小鼠。此外，我们将将这些表型修饰与结构相关联 使用共聚焦显微镜评估的NMJ元素的变化。 AIM 3。我们假设THS可以直接与后vnaptic acetvlcholine受体（ACHR）相互作用 渠道。我们计划直接评估评估肌肉中ACHR通道活性的这种相互作用 纤维使用外部斑块和快速灌注与对照，低甲状腺和高甲状腺小鼠分离 方法论。 这些研究将我们先前的工作扩展到第二阶段，其中开发了各种方法 在过去的两年中，将应用于定义THS在哺乳动物中影响的生理方面 NMJ。数以百万计的美国人（接近2％的人口）受到甲状腺功能障碍的影响。有一个 我们目前对紧张行动基本机制的理解之间的差异 系统和已知提供的有益效果。