Intracellular Regulation Group
Understanding Xenobiotic Transport
David S. Miller, Ph.D.
Principal Investigator and Chief, Toxicology & Pharmacology Laboratory
The Intracellular Regulation Group has focused on the following long-term research goals:
- Defining the basic cellular mechanisms that drive xenobiotic transport in specialized barrier and excretory tissues, such as blood brain barrier, kidney, and liver
- Determining the signals that modulate transport activity
For a large number of therapeutic drugs and environmental pollutants, drug and pollutant metabolites, and waste products of cellular metabolism, these tissues and the transporters they express govern uptake, distribution, and excretion. They are important determinants of drug efficacy on the one hand and drug and pollutant toxicity on the other hand. To design better therapeutic protocols and to be able predict toxic interactions, we must have a thorough understanding of these transport mechanisms and the signals that modulate them.
For the past decade, the group’s research focus has been on understanding the regulation of ATP-driven, xenobiotic efflux pumps (ABC transporters) at the blood-brain barrier. This barrier resides within the brain capillary endothelium and is a limiting factor in treating central nervous system (CNS) disorders, for instance, 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, broad specificity, and high transport potency make P-glycoprotein a primary obstacle to drug delivery to the brain and thus to CNS pharmacotherapy. In recent years, the Intracellular Regulation Group has expanded its focus to include other ABC transporters, MRPs and BCRP, and the blood-spinal cord barrier.
Major area of research:
- Manipulating signaling within the neurovascular unit to improve drug delivery to the CNS
- Understanding how blood-brain barrier transport function is altered by environmental stressors and disease
- Determining the extent to which the barrier and its signaling systems can be therapeutic targets in neurological disease
- Identifying both signals that regulate basal P-glycoprotein transport activity at CNS barriers and the means to activate those signals to improve CNS pharmacotherapy
- Determining how stressors, for example, oxidative stress, xenobiotic stress, and disease, signal changes in ABC transporter expression and activity at CNS barriers
- Devising imaging-based strategies to assess blood-brain and blood-spinal cord barrier function in vitro and in vivo
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.