Role of Aquaporin-4 Water Channels in Cerebral Edema

描述(申请人提供)：脑水肿对创伤性脑损伤、中风和其他神经系统疾病患者的发病率和死亡率有重要影响。然而，治疗方法有限，其机制也鲜为人知。这项研究的长期目标是确定这些机制，并开发更有效的治疗脑水肿的方法。最近的证据表明，脑内主要的水通道--水通道蛋白-4(AQP4)在血脑屏障和脑-脑脊液屏障的星形胶质细胞中大量表达，可能与脑水肿的发生有关。中心假说是AQP4在星形胶质细胞肿胀和脑水肿的发展中起基础作用。为了检验这一假设，本文提出了三个目标。目的1研究水通道蛋白4(AQP4)在创伤性脑损伤模型脑水肿形成中的作用。我们将比较野生型小鼠和AQP4基因缺失小鼠在脑创伤后的脑含水量、颅内压、神经功能和预后。目的研究AQP4在野生型和AQP4缺失型脑片细胞水肿和细胞外空间特性中的作用。目的3重点比较分析野生型小鼠和AQP4缺失小鼠原代培养的星形胶质细胞的细胞体积和离子通量，以及对引起细胞肿胀的病理刺激的反应。这项拟议的研究应该为AQP4在脑水肿发展中的作用提供明确的、机械性的数据。如果AQP4如预期的那样被证明是重要的，那么AQP4功能的调节可能为脑水肿的治疗提供一种新的治疗策略。

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.