Genetic targets of epileptogensis and pharmacoresistance in brain glial cells

颞叶癫痫（TLE）是一种常见的严重慢性神经系统疾病。由于频繁出现耐药性，许多患者不得不接受侵入性海马切除作为控制癫痫发作的唯一选择。因此，迫切需要开发新的药物治疗策略。最近的一些证据表明，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。确定这些亚群并为各自量身定制药物治疗是未来的主要目标，并将使患有这种致残疾病的患者受益。在过去的十年中，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，并且证明是相当不成功的。然而，最近的研究结果表明，神经胶质功能的改变可能在神经元组织的高兴奋性中起重要作用。特别是星形胶质细胞被认为促进癫痫发生和疾病进展，特别是在TLE中。星形胶质细胞在脑水和离子稳态中具有重要的稳态功能，由特定的水和钾通道，AQP4和Kir4.1介导，但也通过特定的转运蛋白，受体介导的Ca2+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，星形胶质细胞通道、受体和细胞内通路）在不同TLE亚组（包括伴海马硬化的TLE （le - hs）和热性癫痫发作后的TLE (le - fs)）中癫痫发作的发生、扩散和维持中发挥关键作用的假设。为此，我们的目标是专注于神经胶质靶点的遗传研究，活的人类癫痫组织和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。研究胶质细胞的功能和基因靶点是一个新兴的领域，可能对耐药TLE患者有直接的临床影响。

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.