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Project 3 - Development and investigation of murine models of channelopathy-associated epilepsy

项目 3 - 通道病相关癫痫小鼠模型的开发和研究

基本信息

批准号：
10477456
负责人：
Jennifer A Kearney
金额：
$ 54.41万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
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：
2018-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477456
关键词：
Action Potentials Acute Address Advanced Development Affect American Animals Anticonvulsants Brain Brain region Cell model Cells Clinical Collaborations Communities Data Detection Development Disease Electrophysiology (science)Epilepsy Equilibrium Etiology Evaluation Functional disorder Genes Genetic Goals Hippocampus (Brain)Impairment In Vitro Induced pluripotent stem cell derived neurons Interneurons Investigation Ion Channel Ion Channel Gating Modeling Mus Mutation Neocortex Neonatal Neurologic Neuronal Dysfunction Neurons Pathogenesis Patients Pattern Pharmaceutical Preparations Pharmacology Phenotype Population Potassium Precision therapeutics Property Regulatory Element Research Seizures Series Slice Sodium Standardization Syndrome System Testing Therapeutic Transgenic Mice Translations Variant base biophysical properties cell type clinically actionable early onset effectiveness evaluation epileptic encephalopathies genetic architecture in vivo in vivo Model in vivo evaluation infancy insight mouse model nervous system disorder precision medicine predictive modeling prevent response synergism voltage

项目摘要

PROJECT SUMMARY – PROJECT 3 Epilepsy is a common neurological disorder that affects over 3 million Americans and has a substantial genetic contribution to its etiology. Mutation of voltage-gated ion channel genes (‘Channelopathies’), particularly voltage-gated sodium (NaV) and potassium (KV) channel genes, have emerged as a major cause of early onset epileptic encephalopathies. These severe epilepsy syndromes are often difficult to treat with existing therapies and are associated with adverse neurodevelopmental sequelae, making them a high priority for better treatment approaches like precision medicine. Functional characterization of a small number of epilepsy- associated voltage-gated ion channel mutations in heterologous expression systems have demonstrated a range of dysfunction, but it is presently difficult to extrapolate these results to in vivo effects. A major goal of our Center is to determine how well in vitro cellular models predict neuronal dysfunction and pharmacological responses in an intact brain. To accomplish this goal, Project 3 will focus on a series of representative mouse models with NaV and KV channel variants that cause prototypical patterns of dysfunction. We hypothesize that differences in the relative contribution of specific channels to excitability in various cell types within neuronal networks determine the net effect on excitation-inhibition balance and influence pharmacological response. Mouse models provide the opportunity to evaluate the effect of channel variants at the whole animal, cellular and network levels, as well as to investigate pharmacological responses. In Aim 1, we will develop mouse models to investigate NaV and KV channel variants associated with early onset epileptic encephalopathy. Mouse lines will be evaluated for neurological phenotypes and pharmacological response in vivo. In Aim 2, we will determine the impact of NaV and KV channel variants on channel properties and intrinsic cell excitability in acutely dissociated neurons isolated from mouse models, and then determine the effectiveness of pharmacological agents at normalizing channel activity and/or cell excitability in these neurons. These results will be compared with similar recordings from heterologous expression systems (Project 1) and patient-specific iPSC-derived neurons (Project 2) to establish important correlations between in vitro and in vivo models. In Aim 3, we will determine the impact of NaV and KV channel variants on intrinsic properties of neurons and consequent effects on network activity in brain slices, and then determine the effectiveness of pharmacological agents at normalizing aberrant cellular and network excitability. Results from Project 3 will provide mechanistic insight into the effects of channel dysfunction in intact brains, and determine therapeutic strategies that normalize excitation-inhibition balance and prevent/reduce seizures. Synergy between this project and Projects 1 and 2 include cross-platform comparisons of the same channelopathy-associated epilepsy variants, which will facilitate translation of results into valuable information for implementation of precision medicine in this common neurological disorder.

项目总结-项目3