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.

尽管在发展神经系统期间严格需要甲状腺激素（THS），但对其作用的分子碱基的理解很少。该项目的长期目标是阐明通过胚胎组织中ThS调节突触功能的分子机制。 t尾的神经肌肉连接（NMJ）是研究神经调节的绝佳系统，因为它在THS存在下因凋亡而死亡。具体目的1。确定胆碱能受体和神经末端的分布在几个发育阶段，该突触系统的解剖学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：负责突触传播的ACHR位于肌肉纤维的极端延髓内。具体目标2。确定THS对突触囊泡回收的急性突触前作用及其与细胞内钙水平的关系。我们将测试观察到的增强的MEPC频率的假设 响应T3的结果，囊泡回收的增强结果。将考虑两个分离的子iam：（a）确定Th在调节囊泡回收中的作用，以及（b）评估核内/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。我们将检验以下假设：THS直接与突触后AC受体相互作用，其次是由T3改变的ACHR动员钙动员会导致ACHR动力活性中的唱片。 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）和常规电生理学。高和低亲和力钙染料将用于评估突触前和突触后区域中的钙水平。这项研究将提供与临床应用有关的信息，包括与T3共同管理和/或使用的治疗。重要的是，神经元凋亡是 现在被认为在中枢神经系统（例如帕金森氏症和阿尔茨海默氏病）以及外围（例如各种神经病和视网膜变性）的多种变性疾病（例如帕金森氏病和阿尔茨海默氏病）中发挥了重要作用。凋亡在这些多样化的生理和病理过程中的关键作用表明，凋亡的药理学和THS的作用将成为生物技术和临床应用的重要靶标。