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.

睡眠呼吸障碍（SDB）是一种影响高达15%的老年人的疾病，与缺血性卒中的患病率和严重程度增加有关。此外，SDB患者卒中后的功能恢复明显较差。SDB背景下神经组织对缺血的脆弱性增加的潜在机制尚不清楚。然而，已经确定神经元优先使用单羧酸盐如乳酸盐和丙酮酸盐作为其能量来源，特别是在能量供应有限的条件下，如中风期间，星形胶质细胞是这种单羧酸盐的主要供应者，并且需要特异性单羧酸盐转运蛋白（MCT）来促进该过程。本申请的目的是检查的基本假设，间歇性缺氧睡眠（CIH）的特点SDB下调表达的单羧酸转运蛋白2（MCT 2）在神经元中，这种变化增加了神经元细胞的脆弱性急性缺氧/缺血（AHI）。基于令人兴奋和高度证实的初步研究结果，我们建议测试这一假设的有效性，并已 开发了3个实验范式，即：（1）使用药理学方法检测成年大鼠在CIH和慢性持续缺氧（CSH）期间海马和皮层中MCT 2和MCT 1表达的变化以及中风模型中MCT 2表达和/或功能降低之间的因果关系。（2）通过转基因方法证实MCT 2在AHI时神经元存活中的作用。（3）探讨MCT 2在神经元缺血耐受中的作用。这些实验将最终证明CIH增加神经组织对AHI的易感性，并且这种现象是由CIH而不是CSH引起的MCT 2表达的不适当降低介导的。此外，对MCT在神经元能量稳态和存活中所起作用的进一步了解可能允许未来开发旨在减少脑血管意外患者梗死面积的药理学策略。