David S. Miller, Ph.D.
Signal Transduction Laboratory / Intracellular Regulation Group
Building 101, Room F189
111 T.W. Alexander Drive
Research Triangle Park, NC 27709
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:
- Determining how transporter expression and drug delivery change in response to xenobiotics acting through ligand activated nuclear receptors, e.g., PXR, CAR, AhR, GR, Nrf2 and ER.
- Understanding mechanisms that underlie changes in transporter expression and function in CNS diseases, e.g. Alzheimer's disease, ALS, Parkinson’s disease.
- Mapping signaling pathways that can be targeted to rapidly and reversibly reduce transporter activity in vivo and thus improve drug delivery to the CNS.
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.
Cartwright TA, Campos CR, Cannon RE, Miller DS. Mrp1 is essential for sphingolipid signaling to p-glycoprotein in mouse blood-brain and blood-spinal cord barriers. J Cereb Blood Flow Metab. 2013;33(3):381-8.
Cannon RE, Peart JC, Hawkins BT, Campos CR, Miller DS. Targeting blood-brain barrier sphingolipid signaling reduces basal P-glycoprotein activity and improves drug delivery to the brain. Proc Natl Acad Sci U S A. 2012;109(39):15930-5.
Campos CR, Schröter C, Wang X, Miller DS. ABC transporter function and regulation at the blood-spinal cord barrier. J Cereb Blood Flow Metab. 2012;32(8):1559-66.
Wang X, Cabrera RM, Li Y, Miller DS, Finnell RH. Functional regulation of P-glycoprotein at the blood-brain barrier in proton-coupled folate transporter (PCFT) mutant mice. FASEB J. 2013;27(3):1167-75.
Wang X, Hawkins BT, Miller DS. Aryl hydrocarbon receptor-mediated up-regulation of ATP-driven xenobiotic efflux transporters at the blood-brain barrier. FASEB J. 2011;25(2):644-52.