The brain depends upon a supply of blood-borne nutrients to maintain its physiological function. A hallmark characteristic of the brain vasculature is an endothelium with tight occluding junctions at positions of cell-cell contact. This absence of spaces between cells prevents bulk diffusion of plasma components into the surrounding tissue. The net result of this "blood-brain barrier" is that influx and efflux of metabolic substrates and nutrients (including glucose, amino acids, and nucleosides) across the brain vasculature must occur via transport systems located in the luminal and abluminal plasma membranes of the endothelial cell. For example, glucose is the primary substrate for brain metabolism and is transported into cells via specific membrane carriers. Under normal glycemic conditions, GLUT1 and GLUT3 are the known members of the glucose transporter family responsible for carrying glucose from the blood and into the cells of the brain. This includes transport across both the luminal and abluminal sides of the endothelial cell and the plasma membranes of the neuronal and glial cells. Although recent studies have greatly expanded our knowledge about glucose transporters in several tissues, much less is currently known about these integral membrane proteins in the brain or how they are regulated in response to pathophysiological conditions. The long-term goals of my research are to characterize the molecular process by which nutrients are transported through the cells comprising the blood-brain barrier (endothelial cells) and the blood-CSF barrier (epithelial cells of the choroid plexus). These goals include an understanding of the molecular identity of the transporters, the membrane sites where transporters are located, the kinetic characteristics of substrate and inhibitor specificity, and, in the future, the mechanisms regulating trans porter activity and expression. Research describing the molecular events of blood-brain transport may be valuable in understanding neurological dysfunctions associated with stroke, diabetes, neurodegenerative diseases and metabolic encephalopathies. Indeed, it could lead to treatment s for minimizing these dysfunctions or for designing therapeutic strategies.
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