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Thyroid hormone signaling

甲状腺激素信号传导

基本信息

批准号：
8929795
负责人：
David Armstrong
金额：
$ 49.14万
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/8929795
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PI 3 K信号转导对甲状腺激素对大脑发育的生理作用的后果。我们的小组最近在哺乳动物甲状腺激素受体TR β的第二锌指中鉴定了两个酪氨酸，这两个酪氨酸对于刺激PI 3 K是必不可少的。当任一酪氨酸突变时，甲状腺激素对PI 3 K的刺激被阻断，而不阻止受体与DNA中的典型甲状腺激素反应元件结合并刺激转录。为了测试直接基因调控和PI 3 K刺激在大脑发育过程中甲状腺激素作用的相对重要性，我们用苯丙氨酸取代这些酪氨酸之一，TRbeta 1中的Y147 F（TRbeta 2中的Y161 F），制作了一种突变敲入小鼠品系。我们对出生后13-17天的小鼠海马脑片中的CA 1神经元进行了电压钳下的全细胞记录，并测量了对Schaffer侧支刺激的突触反应。突变体的突触可塑性被破坏。而TRb在神经元中的表达和垂体中的TSHb表达在突变体中均正常，TRb通过与DNA的直接结合来调节垂体中TSHb的表达。总之，甲状腺激素信号通过PI 3 K似乎是必不可少的兴奋性和抑制性突触的小鼠海马锥体神经元的出生后可塑性的成熟。此外，我们已经表明，甲状腺激素信号通过PI 3 K对突触前介导的突触可塑性有急性影响，我们已经通过用野生型TRb感染突触前神经元来拯救突变体的增强作用来验证这一假设。因此，环境毒物通过PI 3 K破坏甲状腺激素信号传导可能是环境影响人类认知发育的重要机制，我们发现双酚A阻断了这一新的信号传导途径。我们还发现了突变对神经元兴奋性的影响，其与RNAseq确定的活性依赖性基因表达的变化相匹配。与部门的Sheryl Moy博士合作。我们在查佩尔山的精神病学中心，测试这种突变对老鼠在经典学习和记忆模式中的行为的影响。