Aquaporin Water Transport, Extracellular Space, and Epilepsy

水通道蛋白水运输、细胞外空间和癫痫

• 批准号: 8101072
• 负责人: DEVIN K BINDER
• 金额: $ 16.13万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101072
• 关键词: Acute; Address; Adverse effects; Anatomy; Antiepileptic Agents; Astrocytes; Biophotonics; Brain; California; Carrier Proteins; Cell Death; Chronic; Clinical; Clinical Research; Convulsants; Data; Detection; Development; Early Diagnosis; Electroencephalography; Electrophysiology (science); Environment; Epilepsy; Epileptogenesis; Extracellular Space; Fluorescence; Gliosis; Goals; Hippocampus (Brain); Histologic; Human; Image; Immunofluorescence Immunologic; Impaired cognition; In Situ Hybridization; Intracellular Space; Ions; Laboratories; Lead; Learning; Measures; Messenger RNA; Methodology; Methods; Modeling; Molecular; Mouse Strains; Movement; Mus; Neuroglia; Neurologic; Neurons; Neurosciences; Neurosurgical Procedures; Operative Surgical Procedures; Optical Methods; Optics; Osmolar Concentration; Outcome; Partial Epilepsies; Pathology; Patients; Pharmacology; Photobleaching; Pilocarpine; Play; Population; Predisposition; Proteins; Public Health; Regulation; Research; Research Personnel; Resected; Resources; Role; Scientist; Seizures; Specificity; Specimen; Status Epilepticus; Structure; Surface; Techniques; Temporal Lobe Epilepsy; Testing; Time; Tissues; Training; Transgenic Mice; Translational Research; Universities; Up-Regulation; Video Recording; Water; Water Movements; Wild Type Mouse; Work; aquaporin 4; base; cell type; constriction; disability; drug development; extracellular; in vivo; inward rectifier potassium channel; kainate; mouse model; new therapeutic target; novel; novel diagnostics; programs; relating to nervous system; research study; reuptake; social; water channel

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.

描述（由申请人提供）：该项目的重点是开发基于神经胶质细胞对细胞外空间体积和成分的调节的癫痫的新型诊断和治疗方法，以及用于癫痫检测的新型光学方法。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 (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 表达的变化表明 AQP4 可能在癫痫中发挥功能作用。在最近的工作中，我证明 AQP4 缺陷小鼠的癫痫阈值和持续时间显着改变。然而，海马体（对癫痫发作和癫痫至关重要的结构）中 AQP4 的调节和功能尚未得到研究。我建议探索癫痫活动对海马 AQP4 的调节及其在癫痫发生中的功能作用（目标 1 和 2）。此外，我的目的是检验以下假设：脑水的运动可用于开发早期检测癫痫发作的新型光学方法（目标 3）。该提案利用现有的小鼠品系、共聚焦免疫荧光和原位杂交，以及在完善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，专门从事癫痫手术和癫痫研究。我在加州大学欧文分校神经外科系的新实验室获得了机会和资源，这是世界著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，我将学习应用于神经组织的最先进的光学和生物光子技术。我的最终目标是确定抗癫痫药物的新靶点，并衔接转化研究和临床研究，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%），并会导致严重的神经、精神和社会障碍。目前的抗癫痫药物 (AED) 对许多患者无效，即使有效，也会因抑制神经元活动而导致长期认知障碍。神经胶质细胞特异性靶标的识别可能会导致有效且副作用较少的新型 AED 的开发。胶质水通道（水通道蛋白）是新药开发的一个有前途的目标。此外，基于癫痫发作前发生的大脑变化来开发用于癫痫发作检测的新型光学技术将对许多癫痫发作仍不受控制的患者产生直接的临床影响。

项目成果

In vivo detection of cortical optical changes associated with seizure activity with optical coherence tomography.

• DOI: 10.1364/boe.3.002700
• 发表时间: 2012-11-01
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: Eberle MM;Reynolds CL;Szu JI;Wang Y;Hansen AM;Hsu MS;Islam MS;Binder DK;Park BH
• 通讯作者: Park BH

Toward new paradigms of seizure detection.

• DOI: 10.1016/j.yebeh.2012.10.027
• 发表时间: 2013-03
• 期刊: Epilepsy & behavior : E&B
• 作者: Binder DK;Haut SR
• 通讯作者: Haut SR

Laminar-specific and developmental expression of aquaporin-4 in the mouse hippocampus.

• DOI: 10.1016/j.neuroscience.2011.01.020
• 发表时间: 2011-03-31
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Hsu MS;Seldin M;Lee DJ;Seifert G;Steinhäuser C;Binder DK
• 通讯作者: Binder DK

Localization of cortical tissue optical changes during seizure activity in vivo with optical coherence tomography.

• DOI: 10.1364/boe.6.001812
• 发表时间: 2014-04
• 期刊: Biomedical optics express
• 影响因子: 3.4
• 作者: M. Eberle;Carissa L. Reynolds;J. Szu;Yan Wang;Mike S. Hsu;D. Binder;B. H. Park

Improved survival following cerebral edema using a novel hollow fiber-hydrogel device.

使用新型中空纤维水凝胶装置提高脑水肿后的存活率。

• DOI: 10.3171/2012.2.jns111540
• 发表时间: 2012
• 期刊: Journal of neurosurgery
• 影响因子: 4.1
• 作者: McBride,DevinW;Hsu,MikeS;Rodgers,VictorGJ;Binder,DevinK
• 通讯作者: Binder,DevinK