Thyroid hormones and synaptic function

甲状腺激素和突触功能

• 批准号: 7312785
• 负责人: LEGIER V ROJAS
• 金额: $ 35.87万
• 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: 2006-09-01 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7312785
• 关键词: Thyroid; hormones; synaptic; function

Although thyroid hormones (THs) are strictly required during developing nervous system, the molecular bases of their action are poorly understood. The long-term goal of this project is to elucidate the molecular mechanism by which synaptic function is modulated by THs in embryonic tissue. The Neuromuscular junction (NMJ) of tadpole tail is an excellent system to study neuromodulation, because it dies by apoptosis in the presence of THs. Specific Aim 1. Determine the distribution of cholinergic receptors and nerve terminals tadpole tails at several stages of development, The Characterization of the anatomical features of this synaptic system represents the first step towards understanding the non-genomic actions of THs. We will test the hypothesis that the AChRs responsible for synaptic transmission are preferential/y located within the extreme rostral of the muscular fiber. Specific Aim 2. Determine the acute pre-synaptic action of THs on synaptic vesicle recycling and its relationship to intracellular calcium level. We will test the hypothesis that the enhanced mepc frequency observed in response to T3 results from augmented vesicle recycling. Two separated sub-aims will be considered: (a) to determine the role of THs in modulating vesicle recycling, and (b) to assess the role of intracellu/ar calcium level in mediating the actions of TH. Specific Aim 3. Assess the acute postsynaptic action of thyroid hormones on the AChR. We will test the hypothesis that THs interact directly with the postsynaptic AC-receptor and secondly that the calcium mobilization by the AChR that is alter by T3 causes chanties in the AChR kinetic activity. The experiments will include three powerful techniques: Near Infrared (NIR) microscopy, Laser Scanning Confocal Microscopy (LSCM) and conventional electrophysiology. High and low affinity calcium dyes will be used to evaluate calcium levels in the pre- and post-synaptic regions. This study will provide information that is relevant to clinical applications including treatments in which T3 is being co-administrated and/or used. Importantly, neuronal apoptosis is now thought to play a significant role in the pathology of a number of degenerative diseases of the CNS (e.g. Parkinson's and Alzheimer's diseases) as well as in the periphery (for example, various neuropathies and retinal degeneration). The key role of apoptosis in these diverse physiological and pathological processes suggests that the pharmacology of apoptosis and the actions of THs will become important targets for biotechnology and for clinical applications.

尽管神经系统发育过程中严格需要甲状腺激素（TH），但对其作用的分子基础却知之甚少。该项目的长期目标是阐明胚胎组织中 TH 调节突触功能的分子机制。蝌蚪尾部的神经肌肉接头（NMJ）是研究神经调节的绝佳系统，因为它在 TH 存在的情况下会因细胞凋亡而死亡。具体目标 1. 确定胆碱能受体和神经末梢蝌蚪尾部在几个发育阶段的分布，该突触系统的解剖特征的表征代表了理解 THs 非基因组作用的第一步。我们将检验以下假设：负责突触传递的 AChR 优先位于肌纤维的最前端。具体目标 2. 确定 TH 对突触小泡回收的急性突触前作用及其与细胞内钙水平的关系。我们将检验观察到的增强 mepc 频率的假设 响应增强囊泡回收的 T3 结果。将考虑两个独立的子目标：（a）确定TH在调节囊泡再循环中的作用，以及（b）评估细胞内/ar钙水平在介导TH作用中的作用。具体目标 3. 评估甲状腺激素对 AChR 的急性突触后作用。我们将测试以下假设：TH 直接与突触后 AC 受体相互作用，其次，T3 改变的 AChR 的钙动员会导致 AChR 动力学活动发生变化。 实验将包括三种强大的技术：近红外（NIR）显微镜、激光扫描共焦显微镜（LSCM）和传统电生理学。高亲和力和低亲和力钙染料将用于评估突触前和突触后区域的钙水平。这项研究将提供与临床应用相关的信息，包括联合给药和/或使用 T3 的治疗。重要的是，神经细胞凋亡 现在被认为在许多中枢神经系统退行性疾病（例如帕金森病和阿尔茨海默病）以及外周疾病（例如各种神经病和视网膜变性）的病理学中发挥着重要作用。细胞凋亡在这些不同的生理和病理过程中的关键作用表明细胞凋亡的药理学和 TH 的作用将成为生物技术和临床应用的重要目标。