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Cellular Regulation of Sodium-activated Potassium Channels

钠激活钾通道的细胞调节

基本信息

批准号：
10358638
负责人：
LEONARD K KACZMAREK
金额：
$ 36.64万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2022-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10358638
关键词：
Abate Action Potentials Adult Animals Behavior Behavioral Binding Biological Brain Cell membrane Cells Childhood Co-Immunoprecipitations Coupled Cytoplasmic Protein Disease Epilepsy FMR1 FMRP Fluorescence Resonance Energy Transfer Focal Seizure Frontal Lobe Epilepsy Genes Genetic Translation Human Impairment Induced pluripotent stem cell derived neurons Intellectual impairment Ions Knock-in Mouse Knockout Mice Lead Learning Link Malignant - descriptor Measures Messenger RNA Mus Mutation Nervous System Physiology Neuraxis Neurons Neurotransmitter Receptor Pattern Potassium Channel Protein Biosynthesis Proteins Reporter Seizures Signal Transduction Signaling Molecule Signaling Protein Slice Small Interfering RNA Sodium Synapses Syndrome System Testing Therapeutic Intervention Therapeutic Uses Training Translations Ursidae Family Wild Type Mouse Work autism spectrum disorder cell growth regulation childhood epilepsy disease-causing mutation early onset experimental study gain of function mutation hippocampal pyramidal neuron human disease infancy inhibitor mouse model mutant neuronal excitability novel novel therapeutic intervention patch clamp response severe intellectual disability therapeutic lead compound

项目摘要

Human mutations in KCNT1, the gene for the Slack Na+-activated K+ channel result in several different childhood epilepsies, including Malignant Migrating Partial Seizures in Infancy (MMPSI) and Autosomal Dominant Frontal Lobe Epilepsy (ADNLFE). These mutations are gain-of-function mutations that result in enhanced channel opening. Although the seizures may abate with adulthood, all disease-causing Slack mutations are associated with very severe intellectual disability. The intellectual deficits may result from the fact that the large intracellular C-terminus of Slack channels interacts with several cytoplasmic signaling molecules, including Phartr-1, Fragile-X Mental Retardation protein (FMRP) and Cytoplasmic FMRP-Interacting Protein (CYFIP1). The two latter proteins are well known regulators of mRNA translation in neurons. We will record from cortical neurons in cultures and in brain slices from mice expressing the human mutation R455H Slack, to determine how the firing patterns of neurons are altered to produce increased excitability, interictal spikes and spontaneous seizures. We will test the actions of a novel inhibitor of Slack channels to determine whether it reverses the effects of the mutation on neuronal firing and seizures and as well as altered patterns of behavior in the R455H mutant animals. Finally we will determine whether the interactions of Slack channels with their cytoplasmic signaling partners are disrupted in the mutant animals, and whether the ability of activation of Slack channels to modulate mRNA translation in neurons is compromised. This work will provide a biological basis for treatment of these devastating diseases and provide potential lead compounds for therapeutic intervention.

人类KCNT 1基因突变导致几种不同的Na+激活K+通道，儿童癫痫，包括婴儿恶性游走性部分性发作（MMPSI）和常染色体显性额叶癫痫（ADNLFE）。这些突变是功能获得性突变，加强渠道开放。虽然癫痫发作可能会随着成年而减弱，但所有导致疾病的Slack 突变与非常严重的智力残疾有关。智力缺陷可能是由于 Slack通道的大细胞内C末端与几种细胞质信号传导相互作用的事实分子，包括Phartr-1、脆性X智力迟钝蛋白（FMRP）和细胞质FMRP相互作用蛋白（CYFIP 1）。后两种蛋白质是神经元中mRNA翻译的众所周知的调节剂。我们将在培养的皮层神经元和表达人类突变的小鼠的脑切片中记录 R455 H松弛，以确定如何改变神经元的放电模式，以产生增加的兴奋性，发作间期尖峰和自发性癫痫发作我们将测试一种新的松弛通道抑制剂的作用，确定它是否逆转了突变对神经元放电和癫痫发作的影响， R455 H突变动物的行为模式。最后，我们将确定Slack的交互是否通道与其细胞质信号伴侣在突变动物中被破坏，激活Slack通道以调节神经元中mRNA翻译的能力受到损害。这项工作将为治疗这些毁灭性疾病提供生物学基础，并提供潜在的先导化合物进行治疗干预。