Environmental Factor

April 2011

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Research fellow shines at drug development meeting

By Eddy Ball
April 2011

Xueqian (Shirley) Wang, Ph.D.

Wang said that the next step in her work will be looking into the role of the Nrf2 protein in regulation of Pgp and other ATP-binding cassette (ABC) transporters. (Photo courtesy of Steve McCaw)

NIEHS research fellow Xueqian (Shirley) Wang, Ph.D., received a first-place prize for her poster presentation at the Research Triangle Park Drug Metabolism Discussion Group(http://www.rtpdmdg.org/) Exit NIEHS 2011 Winter Symposium, March 17 at the Hilton Raleigh-Durham Airport in Research Triangle Park, N.C. Wang presented the findings of her recent research, "Activating PKC [protein kinase C isoform] Beta1 at the Blood-Brain Barrier Reverses Induction of P-glycoprotein (Pgp) Activity by Dioxin and Restores Drug Delivery to the CNS."

For the past four years, Wang has been a member of the NIEHS Laboratory of Toxicology and Pharmacology Intracellular Regulation Group, headed by Principal Investigator and acting Scientific Director David Miller, Ph.D.(https://www.niehs.nih.gov/research/atniehs/labs/stl/pi/intrareg/index.cfm) Miller and a former postdoctoral fellow in the group, Brian Hawkins, Ph.D., were co-authors on the study.

As part of the group, Wang has investigated the biology of Pgp, an ATP-driven drug efflux pump that is highly expressed at the blood-brain barrier (BBB), where it performs an important protective function by limiting the transport of environmental toxicants into the central nervous system (CNS). However, induction of Pgp can also impede the delivery of therapeutic drugs for treating CNS disorders and for effectively reducing pain in as many as 30 percent of patients.

Enhancing drug delivery

The Miller group has explored ways of targeting signals that increase Pgp expression at the BBB in order to create windows of opportunity for enhancing the transport of therapeutic drugs through the tight barriers in the endothelial cells lining the capillaries within the brain. The researchers are searching for a short-duration intervention along the Pgp activation pathway, so that drug delivery can be improved without leaving the CNS vulnerable any longer than necessary.

In this latest series of experiments, Wang, Hawkins, and Miller investigated whether PKCbeta1-based signaling can reverse CNS drug resistance caused by aryl hydrocarbon receptor (AhR)/dioxin induction of Pgp expression.

The researchers exposed freshly isolated rat brain capillaries to a form of dioxin known as TCDD, which more than doubled Pgp and significantly reduced brain uptake of the drug verapamil, a Pgp substrate. The team then perfused the brain vasculature of the exposed rats with a compound known as dPPA, which specifically activates PKCbeta1.

They determined that this activation at the BBB both reduced basal Pgp activity and reversed the increase in activity triggered by AhR induction of transporter expression. This intervention thus improved brain uptake of verapamil, suggesting that targeting PKCbeta1 may be an effective strategy for improving drug delivery to the brain, even for drug-resistant patients.

In addition to her winning poster, Wang has received several awards in recognition of her research at NIEHS, including NIH Fellows Awards for Research Excellence (FARE) in 2009 and 2010, as well as two first place prizes from the Society of Toxicology in 2010.

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