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Role of Aquaporin-4 Water Channels in Cerebral Edema

Aquaporin-4 水通道在脑水肿中的作用

基本信息

批准号：
7418267
负责人：
GEOFFREY T MANLEY
金额：
$ 29.9万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-05-25 至 2010-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7418267
关键词：
Architecture Astrocytes Blood Blood - brain barrier anatomy Brain Brain Edema Cell Volumes Cells Cerebral Edema Clinical Condition Data Development Edema Equilibrium Extracellular Space Foot Process Glutamates Goals In Vitro Intracranial Pressure Ion Channel Ions Knockout Mice Localized Magnetic Resonance Imaging Measurement Measures Methods Modeling Morbidity - disease rate Mus Nervous System Physiology Neurological outcome Optics Outcome Permeability Physiological Play Potassium Channel Preparation Property Radioactive Research Research Personnel Role Slice Stimulus Stress Stroke Swelling TBI Patients Techniques Testing Tissues Tracer Transgenic Mice Traumatic Brain Injury Water aquaporin 4 brain tissue comparative controlled cortical impact extracellular improved in vivo injured mortality mouse model nervous system disorder novel novel therapeutics programs response water channel

项目摘要

DESCRIPTION (provided by applicant): Cerebral edema contributes significantly to morbidity and mortality in patients with traumatic brain injury, stroke, and other nervous system disorders. However, treatments are limited and the mechanisms are poorly understood. The long-term goal of this research is to identify those mechanisms and to develop a more effective treatment for cerebral edema. Recent compelling evidence has shown that the major brain water channel, aquaporin-4 (AQP4), which is abundantly expressed in astrocytes at the blood-brain and brain-CSF barriers, may contribute to the development of cerebral edema. The central hypothesis is that AQP4 plays a fundamental role in astrocyte swelling and development of cerebral edema. Three aims are proposed to test this hypothesis. Aim 1 will examine the role of AQP4 in the development of cerebral edema in a model of traumatic brain injury. Brain water content, intracranial pressure, neurological function, and outcome will be compared in wildtype mice and AQP4 null mice following brain trauma. Aim 2 will investigate the role of AQP4 in cellular edema and extracellular space properties in wildtype and AQP4 null brain slices using gravimetric, optical, and iontophoretic techniques. Aim 3 will focus on comparative analyses of cell volume and ion flux in primary astrocyte cultures from wildtype mice and AQP4 null mice at baseline and in response to pathological stimuli that induce cell swelling. The proposed research should provide definitive, mechanistic data on the role of AQP4 in the development of cerebral edema. If AQP4 is proven to be important, as anticipated, then modulation of AQP4 function could provide a novel therapeutic strategy for the treatment of cerebral edema.

描述（由申请人提供）：脑水肿对患有创伤性脑损伤、中风和其他神经系统疾病的患者的发病率和死亡率有显着影响。然而，治疗方法有限，而且对其机制知之甚少。这项研究的长期目标是确定这些机制并开发更有效的脑水肿治疗方法。最近令人信服的证据表明，主要的脑水通道水通道蛋白-4 (AQP4) 在血脑和脑脊液屏障的星形胶质细胞中大量表达，可能会导致脑水肿的发生。中心假设是 AQP4 在星形胶质细胞肿胀和脑水肿的发展中发挥重要作用。提出了三个目标来检验这一假设。目标 1 将研究 AQP4 在脑外伤模型中脑水肿发展中的作用。将比较脑外伤后野生型小鼠和 AQP4 缺失小鼠的脑含水量、颅内压、神经功能和结果。目标 2 将使用重量分析、光学和离子电渗技术研究 AQP4 在野生型和 AQP4 缺失脑切片中的细胞水肿和细胞外空间特性中的作用。目标 3 将重点对来自野生型小鼠和 AQP4 缺失小鼠的原代星形胶质细胞培养物中的细胞体积和离子通量进行比较分析，这些结果是基线以及对诱导细胞肿胀的病理刺激的反应。拟议的研究应提供关于 AQP4 在脑水肿发展中的作用的明确的机制数据。如果AQP4被证明是重要的，正如预期的那样，那么AQP4功能的调节可以为治疗脑水肿提供一种新的治疗策略。