Thyroid hormone signaling

甲状腺激素信号传导

基本信息

批准号：
8734155
负责人：
David Armstrong
金额：
$ 55.85万
依托单位：
NATIONAL INSTITUTE OF ENVIRONMENTAL HEALTH SCIENCES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8734155
关键词：
Acute Aging Attention Deficit Disorder Behavior Binding Brain Chemosensitization Cognitive Collaborations DNA DNA Binding Development Dietary Iodine Excitatory Synapse Gene Expression Gene Expression Regulation Genes Genetic Transcription Goals Hippocampus (Brain)Human Inherited Inhibitory Synapse Knock-in Mouse Learning Link Measures Mediating Memory Mental Retardation Molecular Mouse Strains Mus Mutate Mutation Neurologic Neurons Nuclear Receptors Phenylalanine Physiological Pituitary Gland Proteins Psychiatry Relative (related person)Reporting Signal Pathway Signal Transduction Slice Synapses Synaptic plasticity Testing Thyroid Hormone Receptor Thyroid Hormone Receptor Beta Thyroid Hormones Toxic Environmental Substances Tyrosine Whole-Cell Recordings Zinc Fingers bisphenol A deafness high throughput screening hippocampal pyramidal neuron hormone response element iodine deficiency syndrome mutant neurodevelopment neuron development neuronal excitability neurotoxicity novel postnatal presynaptic prevent receptor binding response voltage clamp

项目摘要

We are investigating the consequences of PI3K signaling for the physiological effects of thyroid hormone on brain development. Our group has recently identified two tyrosines in the second zinc finger of the mammalian thyroid hormone receptor, TR beta, that are essential for stimulation of PI3K. When either tyrosine is mutated, PI3K stimulation by thyroid hormone is blocked without preventing the receptor from binding to canonical thyroid hormone response elements in DNA and stimulating transcription. To test the relative importance of direct gene regulation and PI3K stimulation in thyroid hormone action during brain development, we made a mutant knock-in strain of mice with a phenylalanine replacing one of these tyrosines, Y147F in TRbeta1 (Y161F in TRbeta2). We made whole-cell recordings under voltage-clamp from CA1 neurons in hippocampal slices from postnatal day 13-17 mice, and measured synaptic responses to stimulation of Schaffer collaterals. Synaptic plasticity in the mutants was disrupted. However, TRb expression in the neurons and TSHb expression in pituitary, which is fregulated by TRb through direct DNA binding, are both normal in the mutant. In summary, thyroid hormone signaling through PI3K appears to be essential for maturation of postnatal plasticity of both excitatory and inhibitory synapses on mouse hippocampal pyramidal neurons. In addition we have shown that thyroid hormone signaling through PI3K has acute effects on synaptic plasticity that are mediated presynaptically, and we have tested that hypothesis by rescuing potentiation in the mutant by infecting the presynaptic neurons with wild-type TRb. Thus, disruption of thyroid hormone signaling through PI3K by environmental toxicants could be an important mechanism for environmental effects on human cognitive development, and we have discovered that bisphenol A blocks this novel signaling pathway. We have also found effects of the mutation on neuronal excitability that matches changes in activity-dependent gene expression as determined by RNAseq. In collaboration with Dr. Sheryl Moy in the Dept. Psychiatry at UNC Chapel Hill, we are testing the effects of this mutation on the mice's behavior in classical learning and memory paradigms.

我们正在研究PI3K信号传导对甲状腺激素对脑发育的生理影响的后果。我们的小组最近在哺乳动物甲状腺激素受体TRβ的第二个锌指中鉴定了两种酪氨酸，这对于刺激PI3K至关重要。当两种酪氨酸突变时，甲状腺激素的PI3K刺激被阻断，而不会阻止受体与DNA中的规范甲状腺激素反应元素结合并刺激转录。为了测试直接基因调节和PI3K刺激在脑发育过程中甲状腺激素作用中的相对重要性，我们用苯丙氨酸代替了这些酪氨酸之一，在trbeta1中替代了y147f的一种突变型敲入小鼠（y161f in trbeta2中）。我们从产后13-17小鼠的海马切片中的CA1神经元的电压钳下进行了全细胞记录，并测量了对刺激Schaffer侧支的突触反应。突变体中的突触可塑性被破坏。然而，在突变体中，神经元中的TRB表达和垂体中的TSHB表达在TRB中均为正常。总而言之，通过PI3K通过PI3K信号传导对于小鼠海马锥体神经元上兴奋性和抑制突触的产后可塑性的成熟至关重要。此外，我们已经证明，通过PI3K通过PI3K信号传导对突触前介导的突触可塑性具有急性影响，并且我们通过通过感染野生型TRB感染突触前神经元来挽救突变体中的增强剂来检验该假设。因此，环境有毒物质通过PI3K破坏甲状腺激素信号传导可能是对人类认知发展产生影响的重要机制，我们发现双足A阻断了这种新型的信号传导途径。我们还发现了突变对神经元兴奋性的影响，该神经元兴奋性与RNASEQ确定的活性依赖性基因表达的变化相匹配。在UNC Chapel Hill的精神病学系与Sheryl Moy博士合作，我们正在测试这种突变对老鼠在古典学习和记忆范式中的行为的影响。