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：
10596721
负责人：
Nien-Pei Tsai
金额：
$ 1.53万
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 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10596721
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

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.

尽管目前抗癫痫药物不断发展，但美国仍有 300 万人患有癫痫症。药物来提高癫痫发作阈值，三分之一的癫痫患者要么对药物反应不佳，要么仍然处于药物滥用状态。我们的研究旨在促进对癫痫的神经兴奋性失调的理解。我们的目的是改善治疗效果。酸受体（AMPA 受体；AMPAR）是神经系统中最丰富的受体，也是最常见的受体之一。研究发现癫痫患者的兴奋性突触蛋白水平升高，并且尽管如此，药物抑制 AMPAR 已在临床实践中用于缓解癫痫。事实上，目前尚不清楚 AMPAR 的稳态如何介导大脑兴奋性以及如何失调 AMPAR 与癫痫有关。我们最近发现了一种针对 GluA1 亚基的新型泛素 E3 连接酶。 AMPAR，神经前体细胞表达发育下调基因 4 样 (Nedd4-2)。由癫痫相关基因编码，在患者中发现了三个错义突变我们最近发表的文章表明，Nedd4-2 介导神经元和大脑的兴奋性。 AMPAR 依赖方式（Zhu et al., PLOS Genetics, 2017）然而，目前尚不清楚 (1) 是否和 Nedd4-2 如何调节 AMPAR 以影响兴奋性突触传递；以及 (2) 如何与癫痫相关；突变影响 Nedd4-2 在这方面的功能，目标 1 和目标 2 旨在回答这些问题。 Nedd4-2 是肿瘤抑制因子 p53 的靶基因，并受其转录抑制。 p5 的抑制以 Nedd4-2 依赖性方式降低小鼠急性癫痫发作的易感性。结合我们之前的工作，表明 p53-Nedd4-2 作为维持大脑兴奋性的新型信号轴可能通过限制 AMPAR 来研究 p53-Nedd4-2 信号传导和 AMPAR 的调节。使用小鼠颞叶癫痫临床前模型进行泛素化，并确定 p53-Nedd4- 的作用 2 该模型中癫痫发生的信号转导成功完成该项目将改善了解癫痫离子通道失调并促进治疗方法的未来发展癫痫。