Role of Aquaporin-4 Water Channels in Cerebral Edema

描述（由申请人提供）：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，治疗方法是有限的，其机制也知之甚少。这项研究的长期目标是确定这些机制并开发一种更有效的脑水肿治疗方法。最近有令人信服的证据表明，在血脑和脑- csf屏障的星形胶质细胞中大量表达的主要脑水通道水通道蛋白-4 （AQP4）可能参与脑水肿的发生。核心假设是AQP4在星形胶质细胞肿胀和脑水肿的发展中起基础作用。为了验证这一假设，提出了三个目标。目的1将研究AQP4在创伤性脑损伤模型脑水肿发展中的作用。将比较野生型小鼠和AQP4缺失小鼠脑外伤后脑含水量、颅内压、神经功能和预后。目的2将利用重量、光学和离子电泳技术研究AQP4在野生型和AQP4空脑切片细胞水肿和细胞外空间特性中的作用。目的3将重点比较野生型小鼠和AQP4缺失小鼠的原代星形胶质细胞培养物在基线和对诱导细胞肿胀的病理刺激的反应中细胞体积和离子通量的分析。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制数据。如果AQP4如预期的那样被证明是重要的，那么调节AQP4的功能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.