Thyroid hormones and synaptic function

甲状腺激素和突触功能

• 批准号: 7120461
• 负责人: LEGIER V ROJAS
• 金额: $ 27.14万
• 依托单位: UNIVERSIDAD CENTRAL DEL CARIBE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-07 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7120461
• 关键词: Anura; apoptosis; calcium flux; cholinergic receptors; confocal scanning microscopy; developmental neurobiology; electrophysiology; hormone regulation /control mechanism; infrared microscopy; membrane activity; neurogenesis; neuromuscular junction; receptor expression; synapses; synaptic vesicles; thyroid hormones; triiodothyronine

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.

虽然甲状腺激素（TH）在神经系统发育过程中是严格需要的，但对其作用的分子基础知之甚少。本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。蝌蚪尾神经肌肉接头（NMJ）是研究神经调节的理想系统，因为它在TH存在时会发生凋亡。具体目标1。确定胆碱能受体和神经末梢蝌蚪尾巴在几个发展阶段的分布，这个突触系统的解剖特征的表征是理解TH的非基因组作用的第一步。我们将测试的假设，负责突触传递的乙酰胆碱受体是优先/Y位于最喙的肌肉纤维。具体目标2。确定TH对突触囊泡再循环的急性突触前作用及其与细胞内钙水平的关系。我们将检验一个假设，即观测到的增强的mepc频率 在响应T3的结果从增强囊泡回收。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，和（B）评估细胞内钙水平在介导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。我们将测试的假设，TH直接与突触后AC-受体，其次，钙动员AChR，是由T3改变AChR的动力学活动的原因chanties相互作用。 实验将包括三种强大的技术：近红外（NIR）显微镜，激光扫描共聚焦显微镜（LSCM）和传统的电生理学。高和低亲和力钙染料将用于评价突触前和突触后区域中的钙水平。本研究将提供与临床应用相关的信息，包括与T3联合给药和/或使用的治疗。重要的是，神经元凋亡是 现在认为其在CNS的许多变性疾病（例如帕金森病和阿尔茨海默病）以及外周（例如各种神经病和视网膜变性）的病理学中起重要作用。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。