AMPA Receptor Ubiquitination and Pathological Synaptic Hyperexcitability

AMPA 受体泛素化和病理性突触过度兴奋

基本信息

批准号：
10369620
负责人：
Nien-Pei Tsai
金额：
$ 32.93万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
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：
2018-04-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10369620
关键词：
AMPA Receptors Acids Acute Address Affect Antiepileptic Agents Back Brain Calcium Chronic Clinical Trials Complex Data Development Disease Drug resistance Epilepsy Epileptogenesis Fostering Future Genes Genetic Genetic Transcription Genetic study Goals Hippocampus (Brain)Homeostasis Human Genetics Intention Ion Channel Kainic Acid Knock-out Knockout Mice Mediating Membrane Missense Mutation Modeling Molecular Mus Mutation Nervous system structure Neurons Pathologic Patients Permeability Persons Pharmaceutical Preparations Pharmacology Phenotype Pre-Clinical Model Predisposition Protein Isoforms Proteins Publications Publishing Recurrence Regulation Research Research Personnel Role Seizures Signal Transduction Synapses Synaptic Transmission TP53 gene Temporal Lobe Epilepsy Tumor Suppressor Proteins Ubiquitination United States Up-Regulation Work clinical practice design improved in vivo mouse model mutant nerve stem cell neuronal excitability novel novel therapeutics receptor synaptic depression therapy development therapy outcome trafficking ubiquitin-protein ligase

AMPA Receptors Acids Acute Address Affect Antiepileptic Agents Back Brain Calcium Chronic Clinical Trials Complex Data Development Disease Drug resistance Epilepsy Epileptogenesis Fostering Future Genes Genetic Genetic Transcription Genetic study Goals Hippocampus (Brain)Homeostasis Human Genetics Intention Ion Channel Kainic Acid Knock-out Knockout Mice Mediating Membrane Missense Mutation Modeling Molecular Mus Mutation Nervous system structure Neurons Pathologic Patients Permeability Persons Pharmaceutical Preparations Pharmacology Phenotype Pre-Clinical Model Predisposition Protein Isoforms Proteins Publications Publishing Recurrence Regulation Research Research Personnel Role Seizures Signal Transduction Synapses Synaptic Transmission TP53 gene Temporal Lobe Epilepsy Tumor Suppressor Proteins Ubiquitination United States Up-Regulation Work clinical practice design improved in vivo mouse model mutant nerve stem cell neuronal excitability novel novel therapeutics receptor synaptic depression therapy development therapy outcome trafficking ubiquitin-protein ligase

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项目摘要

Epilepsy affects 3 million people in the United States. Despite the development of current antiepileptic drugs to raise seizure threshold, one-third of epilepsy patients either respond poorly to the drugs or remain drug- resistant. Our research aims to facilitate the understanding neuronal excitability dysregulation in epilepsy with the intention to improve therapeutic outcome. We focus on α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPA receptor; AMPAR), the most abundant receptor in the nervous system and one of the well- studied excitatory synaptic proteins. Elevated levels of AMPAR have been observed in epilepsy patients, and pharmacologically inhibiting AMPAR has been used in clinical practice for alleviating epilepsy. Despite all these facts, it remains unclear how the homeostasis of AMPAR mediates brain excitability and how dysregulated AMPAR contributes to epilepsy. We recently identified a novel ubiquitin E3 ligase for the GluA1 subunit of AMPAR, neural precursor cell expressed developmentally downregulated gene 4-like (Nedd4-2). Nedd4-2 is encoded by an epilepsy-associated gene, in which three missense mutations have been identified in patients with epilepsy. Our recent publication demonstrated that Nedd4-2 mediates neuronal and brain excitability in an AMPAR-dependent manner (Zhu et al., PLOS Genetics, 2017). However, it remains unknown (1) whether and how Nedd4-2 modulates AMPAR to affect excitatory synaptic transmission; and (2) how epilepsy-associated mutations affect the functions of Nedd4-2 in this regard. Aim 1 and Aim 2 are designed to answer these questions. Nedd4-2 is a target gene of, and transcriptionally repressed by, the tumor suppressor p53. Our work showed that inhibition of p53 reduces acute seizure susceptibility in mice in a Nedd4-2-dependent manner. This finding, together with our previous work, suggests p53-Nedd4-2 as a novel signaling axis to maintain brain excitability presumably through limiting AMPAR. Aim 3 will study the regulation of p53-Nedd4-2 signaling and AMPAR ubiquitination using a preclinical model of temporal lobe epilepsy in mice, and determine the roles of p53-Nedd4- 2 signaling in epileptogenesis in this model. Successfully accomplishing this project will improve the understanding of ion channel dysregulation in epilepsy and foster future development of therapies in treating epilepsy.

癫痫在美国影响300万人。尽管当前的抗癫痫药发生了提高癫痫发作阈值的药物，癫痫患者中有三分之一对药物反应较差，要么仍然是药物 - 抵抗的。我们的研究旨在促进癫痫中神经元令人兴奋的失调改善治疗结果的意图。我们专注于α-氨基-3-羟基-5-甲基-4-异沙唑pionicic 酸受体（AMPA受体； AMPAR），神经系统中最丰富的受体，也是其中之一研究兴奋性突触蛋白。在癫痫患者中已经观察到AMPAR水平升高，并且药理学抑制AMPAR已在临床实践中用于减轻癫痫。尽管所有这些事实，目前尚不清楚AMPAR的体内稳态如何介导大脑令人兴奋以及如何失调 AMPAR有助于癫痫。我们最近确定了一种新型的泛素E3连接酶，用于GLUA1亚基 AMPAR，神经前体细胞表达的下调基因4样基因（NEDD4-2）。 Nedd4-2是由癫痫相关基因编码，其中已经在患者中鉴定出三个错义突变癫痫。我们最近的出版物表明，NEDD4-2介导神经元和大脑令人兴奋依赖AMPAR的方式（Zhu等，PLOS Genetics，2017）。但是，它仍然未知（1）是否和 NEDD4-2如何调节AMPAR以影响兴奋性突触传播；（2）癫痫相关如何在这方面，突变影响NEDD4-2的功能。 AIM 1和AIM 2旨在回答这些问题。 NEDD4-2是肿瘤抑制p53的靶基因，并在转录上代表。我们的工作表明 p53的抑制作用可降低小鼠中NEDD4-2依赖性的急性癫痫敏感性。这个发现，加上我们以前的工作，建议p53-nedd4-2作为新型信号轴，以保持大脑令人兴奋 AIM 3将研究p53-nedd4-2信号和AMPAR的调节使用小鼠临时叶癫痫的临床前模型的泛素化，并确定p53-nedd4-的作用 2该模型中癫痫发生中的信号传导。成功完成该项目将改善了解癫痫病和促进疗法的未来疗法发展中离子通道失调的理解癫痫。