Role of Aquaporin-4 Water Channels in Cerebral Edema

描述（由申请人提供）：脑水肿是创伤性脑损伤、中风和其他神经系统疾病患者发病率和死亡率的重要因素。然而，治疗是有限的，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（AQP 4），其在血脑屏障和脑-CSF屏障处的星形胶质细胞中大量表达，可能有助于脑水肿的发展。中心假设是AQP 4在星形胶质细胞肿胀和脑水肿的发展中起重要作用。提出了三个目标来检验这一假设。目的1将研究AQP 4在创伤性脑损伤模型中脑水肿发展中的作用。将在脑创伤后的野生型小鼠和AQP 4缺失小鼠中比较脑含水量、颅内压、神经功能和结果。目的2将探讨水通道蛋白4的作用，细胞水肿和细胞外空间的性质，在野生型和水通道蛋白4空脑切片使用重量，光学和离子电渗技术。目标3将集中在比较分析的细胞体积和离子通量的原代星形胶质细胞培养物从野生型小鼠和AQP 4空小鼠在基线和响应于病理刺激，诱导细胞肿胀。拟议的研究应提供明确的，机制的数据，水通道蛋白4在脑水肿的发展中的作用。如果AQP 4被证明是重要的，如预期的那样，那么AQP 4功能的调节可以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.