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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：
9891121
负责人：
Nien-Pei Tsai
金额：
$ 32.94万
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 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9891121
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 Pharmaceutical Preparations Pharmacology Phenotype Pre-Clinical Model Predisposition Protein Isoforms Protein p53 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.

在美国，有300万人患有癫痫。尽管目前抗癫痫药的发展