Genetic targets of epileptogensis and pharmacoresistance in brain glial cells

脑胶质细胞癫痫发生和耐药性的遗传靶标

• 批准号: 194375668
• 负责人: Professor Dr. Christian Steinhäuser
• 金额: --
• 依托单位: Itä-Suomen yliopisto
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2011
• 资助国家: 德国
• 起止时间: 2010-12-31 至 2015-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/194375668?language=en
• 关键词: Genetic; targets; epileptogensis; pharmacoresistance; brain

Temporal lobe epilepsy (TLE) is a common serious chronic neurological condition. Due to frequent pharmacoresistance many patients have to undergo invasive removal of the hippocampus as the only alternative to achieve seizure control. Hence there is an urgent need to develop novel pharmacological treatment strategies.Several recent lines of evidence are pointing towards an important role of genetics in TLE. However TLE is characterized by a complex genetic architecture and probably consists of several different subgroups. To identify these subgroups and tailor pharmacological treatment to the respective is a major future goal and will benefit patients with this disabling condition. During the past decade, most genetic studies focused on polymorphisms in neuronal synaptic ion channel genes, and proved rather unsuccessful. Recent findings however suggest that modified glial function may play an important role in the hyperexcitability of neuronal tissue. Especially astrocytes are supposed to promote epileptogenesis and disease progression in epilepsy, and specifically in TLE. Astrocytes have important homeostatic functions in brain water- and ion homeostasis, mediated by specific water and potassium channels, AQP4 and Kir4.1, but are also critically involved in uptake of neurotransmitters via specific transporters, receptor-mediated Ca2+ signaling and gliotransmitter release.This project tests the hypothesis that astrocytes (more specifically astrocyte channels, receptors and intracellular pathways) play a critical role in generation, spreading, and maintenance of seizures in different TLE subgroups including TLE with hippocampal sclerosis (TLE-HS) and TLE after febrile seizures (TLE-FS). To do this we aim to focus on genetic studies on glia targets, functional studies in living human epileptic tissue and MTLE-HS mouse models, studies on knockout animals, and other functional and molecular biological studies. Investigation of glial function and genetic targets in glia cells, as it will be established in this collaboration, is a new and emerging field that may have direct clinical consequences for patients with pharmacoresistant TLE.

颞叶癫痫(TLE)是一种常见的严重慢性神经系统疾病。由于频繁的药物耐药，许多患者不得不接受侵入性切除海马体作为实现癫痫控制的唯一选择。因此，迫切需要开发新的药物治疗策略。最近的几条证据表明，遗传学在TLE中起着重要作用。然而，TLE具有复杂的遗传结构，可能由几个不同的亚群组成。确定这些亚群并针对不同的亚群进行药物治疗是未来的主要目标，这将使患有这种致残疾病的患者受益。在过去的十年里，大多数遗传学研究都集中在神经元突触离子通道基因的多态性上，并被证明是相当不成功的。然而，最近的发现表明，神经胶质功能的改变可能在神经元组织的过度兴奋性中发挥重要作用。特别是星形胶质细胞被认为促进癫痫的发生和疾病的进展，特别是在TLE中。星形胶质细胞通过特定的水和钾通道AQP4和Kir4.1在脑水和离子稳态中具有重要的动态平衡功能，但也通过特定的转运体、受体介导的钙信号和胶质递质释放参与神经递质的摄取。本项目验证了星形胶质细胞(更具体地说是星形胶质细胞通道、受体和细胞内通路)在不同TLE亚组包括TLE伴海马硬化症(TLE-HS)和TLE热性惊厥后(TLE-FS)癫痫发作的发生、传播和维持中起关键作用的假说。为了做到这一点，我们的目标是专注于神经胶质靶标的遗传学研究，活体人类癫痫组织和MTLE-HS小鼠模型的功能研究，基因敲除动物的研究，以及其他功能和分子生物学研究。研究神经胶质细胞中的神经胶质功能和遗传靶点是一个新的新兴领域，可能会对耐药的TLE患者产生直接的临床后果。