Monocarboylate Transporter, Intermittent Hypoxia and Stroke

单羧酸转运蛋白、间歇性缺氧和中风

• 批准号: 6741095
• 负责人: David Gozal
• 金额: $ 28.2万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-01 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6741095
• 关键词: behavior test; cognition disorders; disease /disorder proneness /risk; genetically modified animals; hypertension; hypoxia; immunocytochemistry; ischemia; laboratory mouse; laboratory rat; lactates; neurons; northern blottings; polymerase chain reaction; pyruvates; respiratory airflow disorder; sleep apnea; stroke; tissue /cell culture; western blottings

Sleep-disordered breathing (SDB), a condition affecting up to 15% of aging people is associated with an increased prevalence and severity of ischemic stroke. Furthermore, the functional recovery after stroke in patients with SDB is markedly worse. The mechanisms underlying the increased vulnerability of neural tissue to ischemia in the context of SDB are unknown. However, it has been well established that neurons preferentially use monocarboxylates such as lactate and pyruvate as their source of energy, in particular during conditions of limited energy supply such as during a stroke, that astrocytes are the predominant purveyors of such monocarboxylates, and that specific monocarboxylate transporters (MCT) are required to facilitate this process. This application aims to examine the fundamental hypothesis that the intermittent hypoxia during sleep (CIH) that characterizes SDB downregulates the expression of monocarboxylate transporter 2 (MCT2) in neurons, and that such changes increase the vulnerability of neuronal cells to acute hypoxia/ischemia (AHI). Based on exciting and highly confirmatory preliminary findings, we propose to test the validity of this hypothesis, and have developed 3 experimental paradigms, namely: (1) To examine changes in MCT2 and MCT1 expression during CIH and chronic sustained hypoxia (CSH) in the hippocampus and cortex of adult rats and the causal relationship between reduced expression and/or function of MCT2 in stroke models using pharmacological approaches. ; (2) To confirm the role of MCT2 in neuronal survival during AHI using transgenic approaches. ; and (3) To examine the role of MCT2 in the tolerance of neurons to ischemia. These experiments will conclusively demonstrate that CIH increases the susceptibility of neural tissue to AHI, and that such phenomenon is mediated by inappropriate decreases elicited by CIH but not CSH in the expression of MCT2. Furthermore, increased understanding of the role played by MCT in neuronal energy homeostasis and survival may permit future development of pharmacological strategies aiming to reduce infarct size in patients suffering from cerebrovascular accidents.

睡眠呼吸的呼吸（SDB），影响高达15％的老年人的疾病与缺血性中风的患病率和严重程度增加有关。此外，SDB患者中风后的功能恢复明显更糟。在SDB背景下，神经组织对缺血的脆弱性增加的机制尚不清楚。但是，已经有很好的确定，神经元优先使用乳酸和丙酮酸等单羧酸盐作为其能源的来源，特别是在诸如中风期间的能源供应有限的条件下，星形胶质细胞是这种单核酸盐的主要供应商，并且需要特定的单核酸酯转运蛋白（MCT）（MCT）。该应用程序旨在研究以下基本假设：SDB表征SDB的间歇性缺氧（CIH）下调了神经元中单羧酸盐转运蛋白2（MCT2）的表达，并且这种变化会增加神经元细胞对急性低氧/缺血性缺血（AHI）的脆弱性。基于令人兴奋且高度确认的初步发现，我们建议检验该假设的有效性，并具有 开发了3种实验范例，即：（1）检查成年大鼠海马和皮层中CIH和慢性持续缺氧（CSH）在中风模型中使用药理学方法中MCT2的降低和/或功能之间的因果关系的变化。 ; （2）使用转基因方法确认MCT2在AHI期间神经元存活中的作用。 ; （3）检查MCT2在神经元对缺血的耐受性中的作用。这些实验将最终证明CIH增加了神经组织对AHI的敏感性，并且这种现象是由CIH引起的不适当降低而介导的，但在MCT2的表达中介导了CSH。此外，对MCT在神经元能量稳态和生存中所扮演的作用的了解增加了可能允许未来开发旨在减少脑血管事故患者的梗死大小的药理学策略。