Although the central nervous system depends of glucose transport (GT) from blood for its energy, the factors modulating hexose transport into brain and the mechanisms by which they act are only partially understood. Studies from the sponsoring institution suggest that chronic changes in plasma glucose cannot solely explain changes in GT across the blood-brain barrier (BBB). Evidence exists that insulin may regulate hexose transport and my preliminary studies are consistent with an inhibitory influence of corticosteroids. Dexamethasone (DEX), a synthetic glucocorticoid, is used as a pharmacologic agent to treat edema in patients with cerebral pathology. Trials using DEX in setting of acute stroke, however, have not consistently documented an improvement in either morbidity or mortality. A decrease in brain GT by DEX would decrease brain glucose concentration and stimulate anaerobic glycolysis which could potentially worsen stroke damage. The effects of glucocorticoids on fuel transport may be important in explaining conflicting clinical observations. Based on these findings, and known effects in peripheral vascular endothelial cells, the regulation of BBB hexose transport by glucocorticoids, and potentially other counter- insulin hormones, will be examined. Initial studies will utilize the Brain Uptake Index (BUI) technique to assess transport in vivo. Subsequent studies will measure transport in isolated cerebral microvessels and cultured microvascular endothelial cells. In addition to measuring GT, where warranted, GT protein number will be quantified. Microvascular endothelial cell cultures will be used to examine mechanisms by which GT is regulated. These studies should provide novel information about the regulation of hexose transport across the BBB. All of the proposed work will be carried out at Boston University School of Medicine in collaboration with investigators expert in brain glucose transport and metabolism, endothelial cell culture, glucocorticoid physiology, and cell biology of GT proteins. This environment will greatly sharpen my research skills and allow me to gain expertise in the study of GT using the most modern techniques. The proposed program will provide me with tremendous opportunities for rigorously studying a specific question with state of the art techniques and expert supervision. It will clearly facilitate my transition into an independent scientific investigator.
| Coderre, Lise; Vallega, Gino A; Pilch, Paul F et al. (2007) Regulation of glycogen concentration and glycogen synthase activity in skeletal muscle of insulin-resistant rats. Arch Biochem Biophys 464:144-50 |
| Chipkin, S R; van Bueren, A; Bercel, E et al. (1998) Effects of dexamethasone in vivo and in vitro on hexose transport in brain microvasculature. Neurochem Res 23:645-52 |
| Coderre, L; Vallega, G A; Pilch, P F et al. (1996) In vivo effects of dexamethasone and sucrose on glucose transport (GLUT-4) protein tissue distribution. Am J Physiol 271:E643-8 |
