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.

癫痫是美国公众的主要经济和个人负担，影响超过 300 万人美国人（占人口的 1-2%）每年诊断出的新病例超过 200,000 例。目前尚无治愈方法。癫痫发作只能使用抗癫痫药物来抑制，但不幸的是，这些药物无效。大约 30% 的患者出现这种情况，并且通常与不良副作用相关。 T型钙通道（T通道）在控制神经兴奋性方面发挥着重要作用。通道在许多神经元的静息膜电位附近开放，使它们能够充当起搏器触发钠依赖性动作电位的电流增加了 T 通道表达和活性。据报道，颞叶癫痫（TLE）动物模型会导致神经过度兴奋。在失神性癫痫中，T 通道活动与丘脑皮质网络振荡有关，从而引起尽管越来越多的证据表明 T 通道在 TLE 和失神中都有作用。对于癫痫，人们对 T 通道活性和表达水平增加的机制知之甚少，促进神经兴奋性和癫痫易感性的增加我们最近发现了一种新的 T 通道。 Ca2+ 通道和趋化受体结构域包含 1 (CACHD1) 蛋白的调节剂。加巴喷丁的主要靶标与 α2α 亚基结构相似，在两者中均高度表达。人类和啮齿类动物的海马和丘脑大脑区域与所有三个 T-具有重叠的表达模式 CACHD1 促进 T 通道的细胞表面表达水平并增加峰值电流。密度，导致神经兴奋性增加和癫痫发作易感性增加。 CACHD1 可预防 γ-丁内酯 (GBL) 诱导的失神癫痫发作并延迟点燃癫痫发作的发作鉴于这些发现，CACHD1 可以促进神经功能的增加。与 TLE 和失神性癫痫相关的兴奋性，使其成为治疗的新目标。将检验我们的中心假设，即 CACHD1 通过增加 T 通道来增加神经兴奋性功能，促进失神性癫痫和 TLE 的发生和严重程度。通过研究，我们将加深对 CACHD1 在缺勤发展中的作用的当前理解癫痫和 TLE，为治疗开发提供了新的靶点。