Aquaporin Water Transport, Extracellular Space, and Epilepsy

项目描述（申请人提供）：本项目主要研究基于神经胶质细胞调节细胞外空间体积和成分的癫痫新诊断和治疗方法，以及癫痫检测的新光学方法。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元环境的影响。水通道蛋白-4 （Aquaporin-4, AQP4）是神经胶质细胞中表达的主要水选择性转运蛋白，人类癫痫标本中AQP4表达的改变提示AQP4可能在癫痫中发挥功能作用。在最近的工作中，我证明了aqp4缺陷小鼠的癫痫发作阈值和持续时间明显改变。然而，AQP4在海马中的调控和功能尚未被研究，海马是癫痫发作和癫痫的关键结构。我建议探讨AQP4在海马中通过癫痫发作活动的调控及其在癫痫发生中的功能作用（Aims 1和2）。此外，我的目标是验证脑水运动可以用于开发早期检测癫痫发作的新型光学方法的假设（目标3）。本研究利用现有小鼠品系、共聚焦免疫荧光和原位杂交、体内药理学、电生理学和成像技术在成熟的癫痫模型中进行研究。我是一名训练有素的临床科学家，专门从事癫痫手术和癫痫研究。我得到了在加州大学欧文分校神经外科的新实验室的机会和资源，这是一个世界知名的神经科学中心和公认的癫痫研究中心。在本提案的培训部分，我将学习最先进的光学和生物光子学技术应用于神经组织。我的最终目标是确定抗癫痫药物的新靶点，并在转化和临床研究之间建立桥梁，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（AEDs）对许多患者无效，即使有效，也可能由于抑制神经元活动而导致长期认知障碍。鉴定胶质细胞特异性靶点可能会导致开发有效且副作用少的新型aed。神经胶质水通道（水通道蛋白）是新药开发的重要靶点。此外，基于癫痫发作前大脑变化的新型光学检测技术的发展，将对许多癫痫发作仍然无法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.