Our overall goal is to understand the basic cellular and molecular mechanisms that regulate xenobiotic transport in specialized barrier tissues of the CNS. The focus is on the blood-brain and blood-spinal cord barriers, which resides within the brain and spinal cord capillary endothelium. These tissues form dynamic interfaces, performing multiple complex tasks, including, control of solute and water exchange between blood and the CNS. They maintain homeostasis by supplying ions and nutrients, removing potentially toxic waste products of metabolism and limiting entry of neurotoxicants. They are also major obstacles to delivery of therapeutic drugs used to treat CNS diseases. Our experimental approach is unique, relying heavily on optical techniques to follow in real-time the movements of fluorescent substrates across cellular membranes and through living cells and intact tissues both in vitro and in vivo. We employ pharmacological and molecular tools and knockout and transgenic animals to map genomic and non-genomic signaling pathways that profoundly alter tissue transport function and thus xenobiotic distribution.
We specifically investigate mechanisms that regulate activity and expression of ABC transporters that are ATP-driven xenobiotic efflux pumps, e.g., P-glycoprotein, multidrug-resistance associated proteins (MRPs) and breast cancer resistance protein (BCRP). Current projects are concerned with:
David S. Miller, Ph.D., is head of the Intracellular Regulation Group and chief of the Laboratory of Toxicology and Pharmacology. He received his Ph.D. in biochemistry from the University of Maine in 1973. He has published over 175 peer-reviewed articles in leading biomedical journals, as well as multiple book chapters. He was a Group Leader at the Michigan Cancer Foundation before joining NIEHS in 1985. Over the past ten years, his research program has provided a detailed description of the mechanisms by which xenobiotic efflux transporters at the blood-brain barrier are regulated.