Daryl L. Davies Associate Professor of Clinical Pharmacy School of Pharmacy

Education:
MA 1992 Biology (Emphasis Molecular Biology) - California State University, Dominguez Hills
Ph.D. 1996 Molecular Pharmacol & Toxicology - University of Southern California, School of Pharmacy

Started at USC: 1999

Research Topics: Drugs of Abuse Pharmacology and Toxicology Applied Drug Discover Early Stage Drug Development

Research Description

Alcoholism is a significant problem in our society with approximately 14 million people in the United States being affected by alcohol. Alcohol causes 100,000 deaths in the US and alcohol related issues are estimated to cost nearly 200 billion dollars annually. Current pharmacological and psychological strategies to treat alcohol related disorders have provided limited success, due in part to the lack of knowledge regarding the initial site(s) and mechanism(s) of alcohol action. A better understanding of where and how alcohol acts is a primary goal of the alcohol research and neuroscience communities.

To address this issue, my laboratory focuses on identifying molecular sites of alcohol action in purinergic receptors (P2XRs).  P2XRs constitute a superfamily of ligand-gated ion channels (LGICs) that have become a focus of investigation in neuroscience and alcohol studies. P2XRs are fast acting, cation-permeable ion channels that are gated by synaptically released extracellular adenosine 5’-triphosphate (ATP). Although in the early stages, building evidence supports a role for purinergic P2XRs in the physiological and behavioral effects of ethanol.  However, there remains a paucity of knowledge regarding the molecular targets and actions of ethanol in P2XRs. 

Due, in part to the lack of pharmacological antagonists, we have taken an alternative approach to this problem by focusing on the development of mutant P2XRs that do not respond to ethanol.  Identification of mutant receptors that can abolish the effects of ethanol without markedly changing agonist response represents the first step in identifying the roles of P2XRs in the physiological and behavioral effects of ethanol.  As a second step in this process my laboratory has begun to incorporate a recombinant lentiviral (rLV) delivery system to investigate the effects of ethanol on overexpressed WT and mutant P2XRs in hippocampal and cortical neurons.  We are also beginning to utilize ethanol insensitive receptors in combination with viral delivery systems as well as knock-in and knockout animals to delineate the role of P2XRs in ethanol-induced behaviors. This line of investigation is of particular usefulness in the purinergic field since subtype selective P2XR antagonists are not well developed, thus hampering our progress in linking specific P2XR subtypes to ethanol-induced behaviors. Although siRNA-mediated protein knockdown and knock-out of P2XRs is transient, the behavioral effect of the receptor knock-out in the animal will be long-lasting.

I am a firm believer in using an interdisciplinary approach. To this end, I work with a team of collaborators which use a combination of pharmacological, molecular, computational chemistry and molecular modeling approaches in combination with electrophysiological characterization of drug action. Along similar lines, my laboratory is gaining recognition at USC for our ability, expertise and patience to train individuals in the use of electrophysiological techniques ranging from 1) Two-electrode voltage clamp in Xenopus oocytes; 2) Whole cell patch clamp in recombinant and dissociated neurons; 3) Hi-throughput automated electrophysiology and 4) The use of lentiviral gene delivery methods. This philosophy has worked well in my laboratory and includes successful training of high school, undergraduate and graduate students as well as faculty members at the School of Pharmacy and across other Schools at USC as well as visiting faculty members from other universities.

Current collaborative projects: 1) Investigations with Dr. Ronald Alkana in the Department of Pharmacology and Pharmaceutical Science (PPSI), USC School of Pharmacy: Together our laboratories investigate the action of alcohol on another superfamily of ligand-gated ion channels (the cys-loop superfamily including GABAA, Glycine, 5HT3 and nACh. The long term goal of this work focuses on the development of pharmacotherapeutic treatment strategies for the treatment of alcohol abuse and alcoholism.

2) Investigations with Dr. Ian Haworth (PPSI), USC School of Pharmacy: This work focuses on the action of alcohol on transporters found in the small intestine. To this end, my laboratory recently made the observation that alcohol has an inhibitory effect on the H+ coupled human peptide transporter 1 (hPepT1). It is plausible that the reduction in transporter capabilities by alcohol directly relates to the dietary as well as immunological deficiencies that many alcoholics experience.

3) Regulatory issues in collaboration with Dr. Frances Richmond, Regulatory Science Program, USC School of Pharmacy: This collaboration has led to a new 12 unit graduate certificate in Pre-Clinical Development in Regulatory Sciences at the School of Pharmacy. The Certificate in Preclinical Development will focus the steps involved in a “bench to bedside” approach to drug discovery and development. The certificate program includes coursework delivered in nontraditional formats such as intensive weekend sessions and uses distance capabilities to capture and web cast lectures and study materials.