Role of CACHD1 in the development of temporal lobe epilepsy and absence epilepsy

CACHD1 在颞叶癫痫和失神癫痫发生中的作用

基本信息

批准号：
10298252
负责人：
MANOJ K PATEL
金额：
$ 39.9万
依托单位：
UNIVERSITY OF VIRGINIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-07-15 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10298252
关键词：
Absence Epilepsy Action Potentials Affect American Animal Model Antiepileptic Agents Aspartic Acid Awareness Brain region Cell surface Characteristics Chemotaxis Development Diagnosis Disease Economics Epilepsy Equilibrium Event Extracellular Domain Fire - disasters Foundations Frequencies Generations Hippocampus (Brain)Human Knock-out Knockout Mice Link Membrane Potentials Modeling Mus Neurons Pacemakers Patients Pattern Pharmaceutical Preparations Play Population Predisposition Proteins Reporting Rest Rodent Role Seizures Severities Signal Transduction Site Sodium Structure T-Type Calcium Channels Temporal Lobe Epilepsy Testing Thalamic structure Tyrosine Unconscious State Up-Regulation base butyrolactone density gain of function knock-down loss of function mouse model neuronal excitability new therapeutic target novel novel therapeutic intervention prevent protein expression receptor side effect therapy development trafficking

项目摘要

Epilepsy is a major economic and personal burden for the American public, affecting over 3 million Americans (1-2% of the population) with over 200,000 new cases diagnosed each year. There is no cure for epilepsy. Seizures can only be suppressed using antiepileptic drugs. Unfortunately, these drugs are ineffective in approximately 30% of patients and are often associated with adverse side effects. T-type calcium channels (T-channels) play an important role in controlling neuronal excitability. T- channels open near the resting membrane potential of many neurons, allowing them to act as pacemaker currents that trigger sodium dependent action potential. Increases in T-channel expression and activity have been reported in animal models of temporal lobe epilepsy (TLE), contributing to neuronal hyperexcitability. In absence epilepsy, T-channel activity has been linked to thalamocortical network oscillations that give rise to spike wave discharges (SWD). Despite growing evidence for a role of T-channels in both TLE and absence epilepsy, little is known about the mechanisms by which T-channel activity and expression levels are increased, facilitating increases in neuronal excitability and seizure susceptibility. We recently discovered a novel T-channel modulator, the Ca2+ channel and chemotaxis receptor domain containing 1 (CACHD1) protein. CACHD1 is structurally similar to 2 subunits, the major target of gabapentinoids. CACHD1 is highly expressed in both human and rodent hippocampal and thalamic brain regions with overlapping expression patterns to all three T- channel subtypes. CACHD1 promotes cell surface expression levels of T-channels and increases peak current densities, leading to an increase in neuronal excitability and increased seizure susceptibility. Knockout of CACHD1 prevents γ-butyrolactone (GBL) induced absence seizures and delays the onset of kindled seizures and reduces seizure durations. In view of these findings, CACHD1 could facilitate increases in neuronal excitability associated with TLE and absence epilepsy, making it a novel target for therapy. In this proposal we will test our central hypothesis that CACHD1 increases neuronal excitability via increases in T-channel function, facilitating the onset and severity of both absence epilepsy and TLE. On completion of these studies we will have advanced our current understanding for the role of CACHD1 in the development of absence epilepsy and TLE, providing a novel target for therapy development.

癫痫病是美国公众的主要经济和个人负担，感情超过300万美国人（占人口的1-2％），每个人都有超过200,000个新壳体。不幸的是，癫痫病可以抑制癫痫发作。在大约30％的患者中，通常与不良副作用有关。 T型钙通道（T通道）在控制神经元的启动性方面起着重要作用。许多神经元的静息膜潜力附近打开的通道，使它们能够充当起搏器触发钠依赖性作用电位的电流增加了T通道和活动在颞叶癫痫（TLE）的动物模型中报道，有助于神经元过度缺席癫痫，T通道活性已与丘脑皮层振荡有关，这些振荡能够使TO to to。尖峰波（SWD），尽管有越来越多的证据癫痫病，对T通道活性和快递水平的机制知之甚少，促进神经元兴奋性和癫痫发作的增加。调节剂，CA2+通道和趋化受体结构域含量为1（CACHD1）类似于2亚基的结构，gabapentinoid的主要靶标在两者中都高度表达人类和啮齿动物海马和淋巴膜大脑区域与所有三个T-的表达模式重叠通道亚型。密度，导致神经元兴奋性不足，癫痫发作的敲除 CACHD1阻止γ-丁基酮（GBL）诱发的杂种，并延迟了点燃的发作鉴于这些发现，CACHD1可以促进癫痫发作持续时间与TLE和缺席癫痫有关的兴奋性，使其成为治疗的新颖靶标。将测试我们的中心假设，即CACHD1通过增加T通道增加神经元兴奋性功能，促进缺席癫痫的发作和严重性。研究我们将对CACHD1在不存在的发展中的作用提出目前的理解癫痫病和TLE，为治疗开发提供了新的靶标。