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

• 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
• 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

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，影响着300多万人。 美国人(占总人口的1%-2%)每年新增确诊病例超过20万例。没有治愈的方法 癫痫。只有使用抗癫痫药物才能抑制癫痫发作。不幸的是，这些药物无效。 在大约30%的患者中，而且往往与不良副作用有关。 T型钙通道在控制神经元兴奋性方面起着重要作用。T- 通道在许多神经元的静息膜电位附近开放，使它们起到起搏器的作用 触发钠依赖动作电位的电流。T通道表达和活性的增加 在颞叶癫痫(TLE)的动物模型中已有报道，导致神经元过度兴奋。在……里面 失神癫痫，T通道活动与丘脑皮质网络振荡有关，导致 棘波放电(SWD)。尽管越来越多的证据表明T-通道在TLE和缺失中都起到了作用 癫痫，人们对T通道活性和表达水平增加的机制知之甚少。 促进神经元兴奋性和癫痫敏感性的增加。我们最近发现了一种新的T-通道 调节剂，钙离子通道和趋化受体结构域包含1(CACHD1)蛋白。CACHD 1是 结构上类似于2亚基，加巴喷丁的主要靶标。CACHD1在这两种组织中都有高表达 人和啮齿动物的海马区和丘脑区对三种T-受体的表达模式都有重叠 通道子类型。CACHD1促进细胞表面T通道的表达水平并增加峰值电流 致密性，导致神经元兴奋性增加和癫痫敏感性增加。淘汰赛 CACH1预防γ-丁内酯诱发的失神发作并延缓点燃发作的发生 并缩短癫痫发作持续时间。鉴于这些发现，CACHD1可以促进神经元数量的增加 兴奋性与TLE和失神癫痫相关，使其成为治疗的新靶点。在这份提案中，我们 将检验我们的中心假设，即CACHD1通过增加T-通道增加神经元的兴奋性 功能，促进失神癫痫和TLE的发病和严重程度。在完成这些任务后 我们的研究将提高我们目前对CACHD在失神发展中的作用的理解 癫痫和TLE，为治疗发展提供了新的靶点。