PATHOPHYSIOLOGY OF BRAIN PH REGULATION

描述：（改编自申请人摘要）： 大脑已经被证明在表现 缺血性脑损伤 尽管间隙pH值的适度降低 可以减轻损伤，严重的酸中毒与显著的 更糟糕的结果。 星形胶质细胞被认为在神经系统的发育中起着积极的作用。 调节大脑pH值，因此这些细胞的存活可能是一个重要的因素。 缺血性损伤发展的决定性因素。 但 星形胶质细胞在缺血性酸碱紊乱中的作用还不清楚。 在正常条件下，这些细胞的细胞内pH值经历快速变化， 对神经元活动的反应。 这种独特的行为 这归因于一个电压敏感的转运系统， 当细胞去极化时，碳酸氢根离子。 因此，pH 星形胶质细胞胞质迅速增加，而间质区室 酸化 鉴于这种转运体的电压依赖性， 可能是大脑酸碱状态的重要贡献者 缺血，其中膜去极化是极端的。 这项提案将解决星形胶质细胞的pH调节机制的作用， 脑缺血的背景。 研究将从第一个开始开始 缺血皮质间质酸碱状态的完整描述， 使用最近开发的用于同时测量pH的方法， 二氧化碳、碳酸氢盐和碳酸盐。 这些数据将有助于 随后的机制研究的设计，其中星形胶质细胞面临的因素 将分别检查脑缺血。 在这里， 微荧光光谱和离子选择性微电极技术将是 结合星形胶质细胞病理生理学的体外研究。 将体外研究得出的结论与直接 从缺血大鼠皮层体内获得的细胞内测量。 这些 研究将阐明大脑中控制脑pH的因素， 缺血 因此，这些结果将有助于了解 缺血性脑损伤机制及治疗进展 在心脏骤停和中风的背景下的策略。

DESCRIPTION: (Adapted from Applicant's Abstract): The acid-base status of the brain has been shown to play a critical role in the manifestation of ischemic brain injury. Although modest reductions in the interstitial pH can mitigate insults, severe acidosis is associated with a significantly worse outcome. Astrocytes are thought to play an active role in the regulation of brain pH, and therefore the survival of these cells may be a determinant factor in the development of ischemic injuries. However, the role of astrocytes in ischemic acid-base disturbances is not understood. Under normal conditions, the intracellular pH of these cells undergoes rapid shifts in response to neuronal activity. This unique behavior has been attributed to a voltage-sensitive transport system that imports sodium and bicarbonate ions when the cells are depolarized. As a result, the pH of astrocyte cytoplasm rapidly increases while the interstitial compartment is acidified. In view of the voltage dependence of this transporter, it is likely to be an important contributor to the acid base status of cerebral ischemia, where membrane depolarization is extreme. This proposal will address the role of astrocyte Ph regulatory mechanisms in the context of cerebral ischemia. Studies will begin with the first complete description of interstitial acid base status in ischemic cortex, using recently developed methods for the simultaneous measurement of pH, carbon dioxide, bicarbonate and carbonate. These data will aid in the design of subsequent mechanistic studies, where factors faced by astrocytes in cerebral ischemia will be examined separately. Here, microspectrofluorometric and ion-selective microelectrode techniques will be combined in an in vitro investigation of astrocyte pathophysiology. Conclusions derived from in vitro studies will be compared against direct intracellular measurements obtained in vivo from ischemic rat cortex. These studies will elucidate the factors that govern brain Ph in cerebral ischemia. The results will therefore contribute to the understanding of the mechanisms of ischemic brain injury and the development of management strategies in the context of cardiac arrest and stroke.