PATHOPHYSIOLOGY OF BRAIN PH REGULATION

大脑 PH 调节的病理生理学

• 批准号: 2669075
• 负责人: MITCHELL CHESLER
• 金额: $ 21.95万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-03-01 至 2001-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2669075
• 关键词: acidity /alkalinity; astrocytes; bicarbonates; brain metabolism; carbon dioxide; cerebral cortex; cerebral ischemia /hypoxia; homeostasis; hypercapnia; interstitial; laboratory rat; microspectrophotometry; tissue /cell culture; voltage /patch clamp

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.

描述：（改编自申请人的摘要）：酸碱状态 大脑已被证明在表现中发挥着关键作用 缺血性脑损伤。 尽管间质 pH 值略有降低 可以减轻损伤，严重的酸中毒与显着相关 更糟糕的结果。 星形胶质细胞被认为在 大脑 pH 值的调节，因此这些细胞的存活可能是 缺血性损伤发生的决定因素。 然而， 星形胶质细胞在缺血性酸碱紊乱中的作用尚不清楚。 正常情况下，这些细胞的细胞内 pH 值会快速变化 因神经元活动而发生变化。 这种独特的行为已经 归因于输入钠和的电压敏感传输系统 当细胞去极化时产生碳酸氢根离子。 结果，pH值 星形胶质细胞的细胞质迅速增加，而间质室 酸化。 考虑到该转运蛋白的电压依赖性， 可能是大脑酸碱状态的重要贡献者 缺血，膜去极化极端。 该提案将解决星形胶质细胞 Ph 调节机制在 脑缺血的背景。 研究将从第一个开始 缺血皮质间质酸碱状态的完整描述， 使用最近开发的同时测量 pH 值的方法， 二氧化碳、碳酸氢盐和碳酸盐。 这些数据将有助于 后续机制研究的设计，其中星形胶质细胞面临的因素 脑缺血则需单独检查。 这里， 显微荧光分光光度法和离子选择性微电极技术将 结合星形胶质细胞病理生理学的体外研究。 体外研究得出的结论将与直接结果进行比较 从缺血大鼠皮层体内获得的细胞内测量结果。 这些 研究将阐明大脑中控制大脑Ph值的因素 缺血。 因此，研究结果将有助于理解 缺血性脑损伤的机制及治疗进展 心脏骤停和中风背景下的策略。