Understanding Xenobiotic Transport
David S. Miller, Ph.D.
Tel (919) 541-3235
Fax (919) 541-5737
email@example.com P.O. Box 12233
Mail Drop F2-03
Research Triangle Park, North Carolina 27709
The Intracellular Regulation Group’s research is focused on defining the basic cellular mechanisms that drive drug and pollutant transport in specialized excretory and barrier tissues, e.g., kidney, liver and blood brain barrier. For a large number of drugs and environmental pollutants, drug and pollutant Metabolism and waste products of cellular metabolism, these tissues govern uptake, distribution and excretion. They are important determinants of drug efficacy on the one hand and drug and pollutant toxicity on the other. A thorough understanding of these transport mechanisms and the signals that modulate them is needed to design better therapeutic protocols and to be able predict toxic interactions. Work over the past several years has been directed at the blood-brain and blood-cerebrospinal fluid (CSF) barriers. To do this group members have devised confocal- and multiphoton-imaging based techniques to follow the transport of fluorescent drugs across intact barrier tissues.
The blood-brain barrier, which resides within the brain capillary endothelium, is a limiting factor in treatment of CNS disorders, e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS. P-glycoprotein, a drug efflux transporter, is a critical element of that barrier. High level of expression, luminal membrane location, wide specificity and high transport potency make P-glycoprotein a primary obstacle to drug delivery into the brain and thus to CNS pharmacotherapy. Current projects involve mapping the signals that modulate activity and expression of P-glycoprotein and other drug efflux transporters in brain capillaries with a view towards manipulating those mechanisms to improve CNS pharmacotherapy, understanding how blood-brain barrier function is altered in disease and determining to what extent the barrier itself can be a target for therapeutics.
The choroid plexus epithelium separates CSF from blood and functions as the "kidney of the CNS," regulating the influx of ions, nutrients and water and the efflux of metabolic wastes. Current projects are concerned with defining the function and regulation of organic anion transporters responsible for the brain to blood transport of xenobiotics and neurotransmitter Metabolism.
Major area of research:
David S. Miller, Ph.D., heads the Intracellular Regulation Group within the Laboratory of Pharmacology. He received his Ph.D. in biochemistry from the University of Maine in 1973. He has published over 150 peer-reviewed articles in leading biomedical journals, as well as several book chapters. He was a Group Leader at the Michigan Cancer Foundation before joining NIEHS in 1985. Over the past ten years the focus of his research has shifted from renal excretory transport to brain barrier tissues.