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Lester R Drewes

Publications and source records attributed to Lester R Drewes.

5 recordsLinked to original sources
PubMed2005

The rat blood-brain barrier transcriptome.

The blood-brain barrier (BBB) is the cellular interface between the circulating blood and neural environment, and is created by apposed endothelial cells and their intercellular tight junctions. Many aspects of how the BBB functions at the molecular level remain unresolved; therefore, we report for the first time a comprehensive gene expression profile of rat brain microvessels using serial analysis of gene expression (SAGE). We assembled a full and quantitative SAGE catalog containing 101,364 tags, of which 33% of the tags matched known genes, 51% matched expressed sequence tags (ESTs) in the Unigene database, and 16% of the tags were unassigned. The transcriptome catalog contains many new and novel transcripts among known BBB genes. A large compliment of junctional proteins and an extensive assortment of facilitated carrier and ATP-dependent transporters are included. To identify microvessel-enriched transcripts, we compared the microvessel SAGE catalog to cortex and hippocampus SAGE catalogs. This resulted in identification of 864 genes, including several known for their abundant expression at the BBB, such as the transferrin receptor (TrnR). Sorting enriched genes based on function revealed groups that encode transporters (11%), receptors (5%), proteins involved in vesicle trafficking (4%), structural proteins (10%), and components of signal transduction pathways (17%). This genomic repertoire emphasizes the unique cellular phenotype existing within the brain and further implicates the BBB as a mediator between the brain and periphery. These results may provide a useful resource and reference point from which to determine the effects of different physiological, developmental, and disease processes on BBB gene expression.

Animals↗
PubMed2005

Modulation of monocarboxylic acid transporter-1 kinetic function by the cAMP signaling pathway in rat brain endothelial cells.

MCT1 (monocarboxylic acid transporter 1) facilitates bidirectional monocarboxylic acid transport across membranes. MCT1 function and regulation have not been characterized previously in cerebral endothelial cells but may be important during normal cerebral energy metabolism and during brain diseases such as stroke. Here, by using the cytoplasmic pH indicator 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein-acetoxymethyl ester, the initial rates of monocarboxylate-dependent cytoplasmic acidification were measured as an indication of MCT1 kinetic function in vitro using the rat brain endothelial cell (RBE4) model of blood-brain transport. The initial rate of L-lactate-dependent acidification was significantly inhibited by 5-10-min incubations with agonists of intracellular cAMP-dependent cell signaling pathways as follows: dibutyryl cAMP, forskolin, and isoproterenol. Isoproterenol reduced V(max) but did not affect K(m) values. The effects of forskolin were completely reversed by the protein kinase A inhibitor H89, whereas H89 alone increased transport rates. Cytoplasmic cAMP levels, measured by radioimmunoassay, were increased by forskolin or isoproterenol, and the effect of isoproterenol was inhibited by propranolol. MCT1-independent intracellular pH control mechanisms did not contribute to the forskolin or H89 effects on MCT1 kinetic function as determined with amiloride, monocarboxylate-independent acid loading, or the transport inhibitor alpha-cyano-4-hydroxycinnamate. The data demonstrate the direct modulation of MCT1 kinetic function in cerebral endothelial cells by agents known to affect the beta-adrenergic receptor/adenylyl cyclase/cAMP/protein kinase A intracellular signaling pathway.

Animals↗
PubMed2005

New frontiers in translational research in neuro-oncology and the blood-brain barrier: report of the tenth annual Blood-Brain Barrier Disruption Consortium Meeting.

The blood-brain barrier (BBB) presents a major obstacle to the treatment of malignant brain tumors and other central nervous system (CNS) diseases. For this reason, a meeting partially funded by an NIH R13 grant was convened to discuss recent advances and future directions in translational research in neuro-oncology and the BBB. Cell biology and transport across the BBB, delivery of agents to the CNS, neuroimaging, angiogenesis, immunotherapy, and gene therapy, as well as glioma, primary CNS lymphoma, and metastases to the CNS were discussed. Transport across the BBB relates to the neurovascular unit, which consists not only of endothelial cells but also of pericyte, glia, and neuronal elements.

Antineoplastic Agents↗
PubMed2003

Molecular features, regulation, and function of monocarboxylate transporters: implications for drug delivery.

The diffusion of monocarboxylates such as lactate and pyruvate across the plasma membrane of mammalian cells is facilitated by a family of integral membrane transport proteins, the monocarboxylate transporters (MCTs). Currently, at least eight unique members of the MCT family have been discovered and orthologs to each have been identified in a variety of species. Four MCTs (MCT1-MCT4) have been functionally characterized. Each isoform possesses unique biochemical properties such as kinetic constants and sensitivity to known MCT inhibitors. Several fold changes in the expression of MCTs may be evoked by altered physiological conditions, yet the molecular mechanisms underlying the regulation of MCTs are poorly understood. Post-translational regulation of MCT1 and MCT4 occurs, in part, by interaction with CD147, an accessory protein that is necessary for trafficking, localization, and functional expression of these transporters. Because of the physiological importance of monocarboxylates to the overall maintenance of metabolic homeostasis, the function of MCTs is significant to several pathologies that occur with disease, such as ischemic stroke and cancer. Finally, the expression of MCT1 in the epithelium of the small intestine and colon and in the blood-brain barrier may provide routes for the intestinal and blood to brain transfer of carboxylated pharmaceutical agents and other exogenous monocarboxylates.

Animals↗