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Gary Goldstein is the President and Chief Executive Officer of Kennedy Krieger Institute. He is also a Professor of Neurology and Pediatrics at Johns Hopkins University, School of Medicine and a Professor of Environmental Health Sciences at Johns Hopkins University, School of Hygiene and Public Health.
Biographical Sketch:
Dr. Goldstein received his M.D. from the University of Chicago in 1966. He served as a Major in the United States Army, before becoming the Director of Pediatric Neurology at the University of Michigan, Ann Arbor.
Research Summary:
The brain is protected from transient, but often large fluctuations in the composition of the blood, by a unique shield known as the blood-brain barrier. This barrier is provided structurally by the uninterrupted wall of brain capillaries, which contain transporter systems to permit entry of essential molecules, and also by metabolic processes that take place in the endothelial cells. This cellular complex, which consists of endothelial cells and a covering layer of the processes of the brain cells known as astrocytes, is a target tissue in a number of insults to the brain, particularly in immature animals. Therefore, understanding the metabolic events that promote these insults to the barrier and how they are regulated will aid in attempts to protect the brain from injury.
Dr. Goldstein has been concerned with wide-ranging studies of transporter systems in brain capillaries, and both structural and metabolic aspects of the blood-brain barrier. To investigate the metabolic basis of blood-brain barrier vulnerability, he and his colleagues devised methods to isolate microvessels from immature brain, propagate endothelial cells in tissue culture, and co-culture endothelial cells and astrocytes to model angiogenesis in vitro. Their findings suggest that interactions between endothelial cells and astrocytes are important for blood-brain barrier function: alterations in calcium homeostasis and second messenger action appear to play a major role in the disruption of these cellular interactions after injury. For example, calcium entry is increased in both isolated microvessels and cultured endothelial cells exposed to the toxicant, inorganic lead. Further, lead at very low concentrations may act as a calcium agonist in the activation of calmodulin and protein kinase C. Once activated by divalent cations, calmodulin regulates a number of transporters and enzymes. Binding of lead to calmodulin resulted in perturbations in potassium permeability, as well as stimulation of phosphodiesterases and specific astrocyte phospholipases. Moreover, in preparations in vitro, activation of protein kinase C inhibits the formation of capillary-like structures. Taken together, these findings implicate defects in second messenger function in the pathogenesis of the microvascular dysfunction that occurs in an immature brain after injury.
Recent Publications/Presentations:
Wilson MA, Johnston MV, Goldstein GW, Blue ME. Neonatal lead exposure impairs development of rodent barrel field cortex. Proceedings of the National Academy of Sciences of the United States of America. 2000 May 9;97(10):5540-5.
Kim KA, Chakraborti T, Goldstein GW, Bressler JP. Immediate early gene expression in PC12 cells exposed to lead: requirement for protein kinase C . Journal of neurochemistry. 2000 Mar;74(3):1140-6.
Johnston MV, Goldstein GW. Selective vulnerability of the developing brain to lead. Current opinion in neurology. 1998 Dec;11(6):689-93.
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