Aquaporin Water Transport, Extracellular Space, and Epilepsy

描述(申请人提供)：该项目致力于开发新的癫痫诊断和治疗方法，基于神经胶质细胞对细胞外空间体积和成分的调节，以及用于癫痫检测的新的光学方法。越来越多的证据支持神经胶质细胞在癫痫中的功能作用，至少部分是通过它们对神经环境的影响。水通道蛋白-4(Aquaporin-4，AQP4)是神经胶质细胞表达的主要水选择性转运蛋白，在人类癫痫标本中的表达变化提示AQP4可能在癫痫的发病机制中发挥作用。在最近的工作中，我证明了AQP4缺陷小鼠显著改变了癫痫发作阈值和持续时间。然而，AQP4在海马区的调节和功能尚未被研究，海马区是癫痫和癫痫的关键结构。我建议探索癫痫发作活动对海马区AQP4的调节及其在癫痫发生中的功能作用(目标1和2)。此外，我的目标是验证这样一种假设，即大脑水分的运动可以用来开发新的光学方法来早期检测癫痫发作(目标3)。这一建议利用了现有的小鼠品系、共聚焦免疫荧光和原位杂交，以及在已建立的癫痫模型中的体内药理学、电生理学和成像。我是一名训练有素的临床医生兼科学家，专门从事癫痫外科和癫痫研究。我在加州大学欧文分校神经外科的新实验室获得了机会和资源，这是一个世界著名的神经科学中心和公认的癫痫研究中心。在这项计划的培训部分，我将学习应用于神经组织的最先进的光学和生物光子学技术。我的最终目标是为抗癫痫药物确定新的靶点，并在翻译和临床研究之间架起桥梁，以开发用于患者的光学癫痫检测。相关性：癫痫是一个主要的公共卫生问题，因为它很常见(约占人口的1%)，并导致严重的神经、精神和社会残疾。目前的抗癫痫药物(AED)对许多患者无效，即使有效，也会由于抑制神经元活动而导致长期的认知损害。识别胶质细胞特异性靶点可能会导致开发出有效且副作用较少的新型AEDs。神经胶质水通道(水通道蛋白)是新药开发的一个很有前途的靶点。此外，基于癫痫发作前大脑变化检测癫痫发作的新光学技术的发展，将对许多癫痫发作仍未得到控制的患者产生直接的临床影响。

DESCRIPTION (provided by applicant): This project is focused on developing novel diagnostics and treatments for epilepsy based on glial cell regulation of extracellular space volume and components, and novel optical methods for seizure detection. Accumulating evidence supports a functional role for glial cells in epilepsy, at least in part via their effect on neuronal environment. Aquaporin-4 (AQP4) is the main water-selective transporting protein expressed in glial cells, and alterations in AQP4 expression in human epileptic specimens suggest that AQP4 may play a functional role in epilepsy. In recent work, I demonstrated that AQP4-deficient mice have markedly altered seizure threshold and duration. However, the regulation and function of AQP4 in the hippocampus, a structure critical to seizures and epilepsy, have not yet been studied. I propose to explore the regulation of AQP4 in the hippocampus by seizure activity and its functional role in epileptogenesis (Aims 1 and 2). Furthermore, I aim to test the hypothesis that movement of brain water can be used to develop novel optical methods for early detection of seizures (Aim 3). This proposal utilizes available mouse strains, confocal immunofluorescence and in situ hybridization, and in vivo pharmacology, electrophysiology and imaging in well-established epilepsy models. I am a fully-trained clinician-scientist specializing in epilepsy surgery and epilepsy research. I have been given the opportunity and resources for my new laboratory in the Department of Neurological Surgery at the University of California, Irvine, a world-renowned center for neuroscience and a recognized center for epilepsy research. In the training portion of this proposal, I will learn state-of-the-art optics and biophotonics techniques applied to neural tissue. My ultimate goals are to identify novel targets for antiepileptic drugs, and bridge translational and clinical research to develop optical seizure detection for use in patients. RELEVANCE: Epilepsy is a major public health problem as it is common (about 1 % of population) and causes severe neurological, psychiatric, and social disability. Current antiepileptic drugs (AEDs) are ineffective in many patients and even when effective can cause long-term cognitive impairment due to suppression of neuronal activity. Identification of glial cell-specific targets may lead to the development of novel AEDs that are effective and have fewer side effects. Glial water channels (aquaporins) are a promising target for new drug development. In addition, development of novel optical techniques for seizure detection based on changes in the brain that occur just prior to seizure onset will have a direct clinical impact on the many patients whose seizures remain uncontrolled.