William Clarke, Ph.D.
Research in our lab is focused on understanding the cellular and molecular mechanisms of drug efficacy (the ability of a drug to produce a response, following interaction with a receptor). Together with my long-time collaborator, Dr. Kelly Berg, our work has employed a combination of quantitative pharmacological, biochemical, molecular, cellular and behavioral approaches to understand how drugs activate G protein coupled receptors (GPCRs) to regulate cellular signaling and change behavior. We are especially interested in ligand-independent (constitutive) receptor activity, inverse agonism, and functional selectivity (also known as biased agonism - the ability of different ligands that act at the same receptor to produce different responses). We are also interested in how these pharmacological parameters differ with cell phenotype and cell physiological state. For the past several years our studies have centered upon the regulation and function of peripheral opioid receptors expressed by peripheral pain-sensing neurons and their role as potential targets for safer treatments for pain. Inhibition of these pain-sensing neurons can produce powerful analgesia (think local anesthetics). Opioid drugs that are modified to be peripherally-restricted so that they do not enter the CNS would be effective analgesics for some forms of pain (post-surgical, inflammatory, etc.) that involve activity of the peripheral pain-sensing neurons but would be devoid of the serious adverse effects that are due to opioid action on receptors expressed in the CNS (respiratory depression, addiction, abuse, sedation, etc.). We utilize a complementary system to study opioid receptor function and regulation in peripheral pain-sensing neurons that includes study of peripheral sensory neurons, derived from the trigeminal and dorsal root ganglia, in culture and well as in vivo in behavioral assays of pain. The combination of ex vivo (primary neuronal cultures) and in vivo studies is a powerful approach that allows for rigorous, quantitative, pharmacological analyses of cellular signaling systems and assessment of the physiological relevance of findings obtained from ex vivo studies.
Postdoctoral Fellowship -
Mount Sinai School of Medicine
Wayne State University School of Medicine
The University of Texas Health Science Center at San Antonio, Pharmacology, San Antonio
Assistant Professor -
Mount Sinai School of Medicine
Instruction & Training
- 6/2012 - Present, Membership on Supervising Committee, The University of Texas Health Science Center at San Antonio
- 7/2011 - Present, Ph.D. Dissertations Directed, The University of Texas Health Science Center at San Antonio
- 6/2011 - Present, Ph.D. Dissertations Directed, The University of Texas Health Science Center at San Antonio
- 7/2010 - Present, Post-Doctoral Student Supervision, The University of Texas Health Science Center at San Antonio
- 1/2010 - Present, Membership on Supervising Committee, The University of Texas Health Science Center at San Antonio
- 6/2008 - Present, Receptors-Effectors (Summer Undergraduate Course), The University of Texas Health Science Center at San Antonio
- 1/2007 - Present, Membership on Supervising Committee, The University of Texas Health Science Center at San Antonio
Research & Grants
Funding Agency ASPET Title ASPET Fellowship Program for Undergraduate Students Status Active Period 6/2007 - Present Role Principal Investigator Grant Detail Funding Agency NIH/NIA Title Aging, peripheral pain and analgesia Status Active Period 2/2015 - 1/2018 Role Principal Investigator Grant Detail We propose to evaluate the effect of aging on the function and regulation of peripheral, pain-sensing neurons and opioid receptor systems expressed by these neurons. Our ultimate goal is to develop analgesics with improved efficacy and safety for use in the elderly population Funding Agency NIH/NGMS Title Regulation of Kappa opioid receptor-mediated signaling and peripheral analgesia Status Active Period 1/2014 - 11/2017 Role Principal Investigator Grant Detail The major goal of this project is to study the regulation of kappa opioid receptor (KOR) signaling systems by the MAPKinases, ERK and JNK, as well as acute desensitization of KOR agonist signaling in peripheral sensory neurons, using primary cultures of adult rat sensory neurons and a behavioral model of nociception Funding Agency NIH/NIDA Title Regulation of DOR-KOR heteromer formation in pain-sensing neurons Status Active Period 9/2014 - 8/2017 Role Principal Investigator Grant Detail We propose to validate approaches to disrupt the formation or function of delta-kappa opioid receptor heteromers expressed by pain-sensing neurons in vivo and ex vivo.