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| David S. Miller, Ph.D., Investigator |
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Dr. Miller received his Ph.D. in Biochemistry in 1973 from the University of
Maine, were he studied nutrient uptake pathways in intestine. During his
postdoctoral training with William Kinter at the Mount Desert Island Biological
Laboratory, he identified a Ca-ATPase as the biochemical basis for DDT-induced
eggshell thinning in birds. Dr. Miller developed an independent research
program focused on interactions between toxicants and transporters in kidney
and intestine. He moved to the Michigan Cancer Foundation in 1981 as Chief,
Laboratory of Metabolic Control. In 1985, he moved to NIEHS, where he is
currently Head, Intracellular Regulation Group and Associate Chief, Laboratory
of Pharmacology. Dr. Miller's group studies regulation of blood-brain barrier
drug efflux transporters, with a focus on improving pharmacotherapy of CNS
diseases, including cancer and epilepsy.
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Staff:
- Brian Hawkins, Ph.D., Postdoctoral Fellow, (919) 541-3999 hawkinsb2@niehs.nih.gov
- Robert Rigor, Ph.D., Postdoctoral Fellow, (919) 541-4648 rigorr@niehs.nih.gov
- Destiny Sykes, M.S., Chemist, (919) 541-0045 sykes1@niehs.nih.gov
- Xeuqian Wang, Ph.D., Post-Doctoral IRTA, (919) 541-3318 wangx4@niehs.nih.gov
Research Interests:
Uptake, distribution and excretion of a large number of toxicants and therapeutic drugs are largely governed by specific transporters in specialized excretory and barrier tissues, e.g., kidney, liver and blood brain barrier. They are important determinants of drug efficacy on the one hand and drug and pollutant toxicity on the other. Our recent work has been directed at defining mechanisms that modulate transporter activity and expression at the blood-brain and blood-cerebrospinal fluid (CSF) barriers. We have devised confocal- and multiphoton-imaging based techniques to follow the transport of fluorescent drugs across intact barrier tissues. Current projects are focused on P-glycoprotein, an ATP-driven drug efflux transporter, that is a critical component of the blood-brain 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 of, e.g., neurodegenerative diseases, epilepsy, brain cancer, and neuro-AIDS. We are 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.
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Selected Recent Publications:
Miller DS, Bauer B and Hartz AMS (InPress) Modulation of P-glycoprotein at the blood-brain barrier: Opportunities to improve CNS pharmacotherapy., Pharmacol.
Hartz AMS, Bauer B, Block ML, Hong J-S and Miller DS (InPress) Diesel exhaust particles induce oxidative stress, pro-inflammatory signaling, and P-glycoprotein upregulation at the blood-brain barrier, FASEB.
Bauer B, Hartz AM, Yang X, Lucking, JR, Pollack GM, Fricker G, Miller DS (2008) Coordinated nuclear receptor regulation of the efflux transporter, Mrp2, and the phase-II metabolizing enzyme, GSTÀ, at the blood-brain barrier, J Cerebral Blood Flow Metab 28, 1222-1234.
Bauer B, Hartz AM, Pekcec A, Toellner K, Miller DS, Potschka H. (2008) Seizure-induced upregulation of P-glycoprotein at the blood-brain barrier through glutamate and COX-2 signaling, Mol Pharm 73, 329-41.
Bauer, B., Hartz, A.M.S., and Miller D.S (2007) TNF-a and endothelin-1 increase P-glycoprotein expression and transport activity at the blood-brain barrier, Mol. Pharm 71, 667-75.
Bauer B, Yang X, Hartz AM, Olson ER, Zhao R, Kalvass JC, Pollack GM, Miller DS (2006) In vivo activation of human PXR tightens the blood-brain barrier to methadone through P-glycoprotein upregulation, Mol Pharm 70, 1212-1219.
All Selected Publications
Contact Information:
Dr. David S. Miller
NIEHS - MD F2-03
P.O. Box 12233
Research Triangle Park, NC 27709-
Telephone: (919) 541-3235 (office),
(919) 541-5737 (fax)
Email: miller@niehs.nih.gov
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