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MODULATION OF MONOCARBOXYLIC ACID TRANSPORTERS IN BRAIN

脑中单羧酸转运蛋白的调节

基本信息

批准号：
6718958
负责人：
LESTER Richard DREWES
金额：
$ 30.75万
依托单位：
UNIVERSITY OF MINNESOTA DULUTH
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-01 至 2006-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/6718958
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

项目摘要

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.

乳酸和相关的单羧酸是重要的