MODULATION OF MONOCARBOXYLIC ACID TRANSPORTERS IN BRAIN

脑中单羧酸转运蛋白的调节

• 批准号: 2883737
• 负责人: LESTER Richard DREWES
• 金额: $ 22.43万
• 依托单位: UNIVERSITY OF MINNESOTA DULUTH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-08-01 至 2005-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2883737
• 关键词: animal genetic material tag; astrocytes; brain metabolism; carboxylate; cerebellum; cerebral cortex; cerebral ischemia /hypoxia; gene induction /repression; hippocampus; immunocytochemistry; laboratory rat; lactic acidosis; membrane transport proteins; neurogenetics; neurons; nutrition related tag

DESCRIPTION: Lactate and related monocarboxylic acids are important substrates and metabolic products of brain metabolism. Under conditions such as starvation, high fat consumption, and early development (newborn or suckling neonates), monocarboxylates such as lactate, pyruvate and ketone bodies may be extracted from the blood and used by the brain as fuels. Recent evidence suggests metabolic coupling occurs between astrocytes and neurons whereby lactate produced by astrocytes is utilized by neurons during neural activation. The overall objective of this proposal is to characterize the monocarboxylic acid transporters in brain and their role in blood-brain transport and cerebral metabolism. This includes molecular identification of the membrane proteins responsible for transporting monocarboxylic acids (lactic, pyruvic, acetoacetic and ^D- hydroxybutyric acids) across the plasma membranes of endothelial cells, astrocytes, and neurons; characterization of their cellular location, expression, regulation, and role in cerebral metabolism. The principal hypotheses to be tested are that: 1) the requisite monocarboxylate transporters (MCTs) for metabolic coupling between astrocytes and neurons are present in rat brain cortex, hippocampus and cerebellum; 2) upregulation of at least two separate MCT genes (MCT1 and MCT2) occurs independently (spatially and temporally) during postnatal development; 3) animals with elevated expression of brain MCTs from dietary manipulations are more resistant to hypoxic/ischemic cell damage than control animals; and 4) brain lactic acidosis associated with hypoxia/ischemia induces increased expression of MCTs. Specific antibodies and oligonucleotide probes for MCT1 and MCT2 will be used to analyze and quantify transporter proteins and mRNA. mRNA will be determined by ribonuclease protection assays and by in situ hybridization. MCT proteins will be determined by immunoblot detection and light and electron immunocytochemistry. The expression of MCTs in response to dietary alterations and global forebrain ischemia will be examined. Animals with experimentally increased levels of MCTs will be assessed for their ability to resist neurological damage following global forebrain ischemia. The genomic sequence of MCT1 and MCT2 will be closed and characterized and other brain MCTs will be identified. These proposed studies will contribute to a better understanding of the metabolic interrelationships among cells of the brain and therefore may lead to improved therapies, or preventive measures for patients with stroke or neurodegenerative disorders.

描述：乳酸和相关的单羧酸很重要 脑代谢的底物和代谢产物。 在条件下 例如饥饿，高脂肪消耗和早期发展（新生儿或 哺乳新生儿），单羧酸盐，例如乳酸，丙酮酸和酮 可以从血液中提取物体，并被大脑用作燃料。 最近的证据表明，代谢耦合发生在星形胶质细胞和 神经元由星形胶质细胞产生的神经元被神经元在 神经激活。 该提议的总体目的是 表征大脑中的单羧酸转运蛋白及其在 血脑运输和大脑代谢。 这包括分子 识别负责运输的膜蛋白 单羧酸（乳酸，丙酮，乙酸乙酸和d-羟基苯甲酸 酸）穿过内皮细胞，星形胶质细胞和 神经元；表达其表达的表征 调节和在脑代谢中的作用。 主要假设是 测试的是：1）必要的单羧酸盐转运蛋白（MCT） 星形胶质细胞和神经元之间的代谢耦合存在于大鼠脑中 皮质，海马和小脑； 2）至少两个独立的上调 MCT基因（MCT1和MCT2）独立发生（在空间和时间上） 在产后发展期间； 3）大脑表达升高的动物 饮食操纵的MCT对低氧/缺血细胞具有更耐药性 损害比控制动物； 4）与 缺氧/缺血诱导MCT表达增加。 特定抗体 MCT1和MCT2的寡核苷酸探针将用于分析和 定量转运蛋白和mRNA。 mRNA将由 核糖核酸酶保护测定和原位杂交。 MCT蛋白 将通过免疫印迹检测以及光和电子确定 免疫细胞化学。 MCT响应饮食的表达 将检查改变和全球前脑缺血。 动物 将评估实验上提高的MCT水平的能力 在全球前脑缺血之后抵抗神经系统损害。 这 MCT1和MCT2的基因组序列将被封闭和表征以及其他 将确定脑MCT。 这些拟议的研究将有助于 更好地了解细胞之间的代谢相互关系 大脑，因此可能导致 改善中风患者或预防措施或预防措施 神经退行性疾病。