UTHSCSA Faculty Profiles v1.0
Clarke, William P
Graduate School of Biomedical Sciences
Pharmacology
(210) 567-4171
clarkew@uthscsa.edu
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| 9/2008 - Present |
Professor |
The University of Texas Health Science Center at San Antonio, Pharmacology, San Antonio, TX |
| Year |
Degree |
Discipline |
Institution |
| 1984 |
PhD |
Physiology |
Wayne State University School of Medicine
Detroit , MI |
| 1979 |
MS |
Biology |
Northeastern University
Boston , MA |
| 1974 |
BS |
Chemistry |
Boston College
Boston , MA |
| |
Postdoctoral Fellowship |
Pharmacology |
Mount Sinai School of Medicine
New York , NY |
Drug efficacy -
Work in my lab centers on questions concerning the molecular nature of drug efficacy and the cellular mechanisms by which efficacy can be regulated. Drug efficacy is defined as the ability of a drug to produce a response or an effect. According to traditional receptor theory (see equation #1), the magnitude of an effect (E) produced when an agonist at a specified concentration ([A]) interacts with a receptor is a function (?) of the stimulus (S) produced by the agonist and depends upon 4 factors. Two of these are chemical properties of the agonist itself unique for each ligand-receptor pair; the affinity related parameter, Kd and ?intrinsic efficacy?, e (e describes the capacity of a drug to produce a receptor ?stimulus? {which can be thought of as a conformational change in the receptor} which is transmitted to the signal transduction components of the cell). The remaining two parameters are cell or tissue dependent properties; receptor density, RT and an undefined function, ? (typically a hyperbola
{S/(S+a)}), that describes the efficiency of signal transduction. Thus, cellular mechanisms that influence drug efficacy are those that regulate any or all of these four parameters.
Equation #1
Brain slices and cell culture (primary and cell lines) systems are used as models for our studies along with some in/ex vivo studies. Cellular consequences of receptor activation (i.e. ?response?) are studied using a multifaceted approach including biochemical (receptor binding, quantitative receptor autoradiography, immunocytochemistry, enzyme activity assays, measurement of 2nd messenger levels [cAMP, phosphoinositides, calcium, arachidonic acid], protein phosphorylation, etc.), molecular (heterologous expression, site-directed mutagenesis, chimera, baculovirus etc.) and imaging (fluorescence, FRET) techniques.
Cellular factors involved in the regulation of drug efficacy that are under investigation include the consequences of activation of other receptor systems on cells (so-called ?cross-talk? between receptor systems) and mechanisms of desensitization (homologous and heterologous). Since single receptor subtypes typically couple to multiple effector pathways in cells, we are especially interested in effector pathway-dependent efficacy and its differential regulation. With the recent discovery that G protein coupled receptor systems display constitutive activity (in the absence of an activating ligand) and the existence of ligands with negative intrinsic efficacy (i.e. ?inverse agonists?), we are studying properties of inverse agonists. An understanding of the nature of drug efficacy and the factors by which it is regulated is essential for the design of rational treatment regimens in clinical situations. |
| Date |
Description |
Institution |
# Students |
| 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 |
|
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| 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) |
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|
|
| 1/2007 - Present |
Membership on Supervising Committee |
The University of Texas Health Science Center at San Antonio |
|
|
Federal |
| 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. |
| Funding Agency |
NIH/IIMS-CTRC Pilot Award |
| Title |
Efficacy of P7C3-A20 to prevent pain symptoms of chemotherapy-induced peripheral neuropathy |
| Status |
Active |
| Period |
5/2015 - 4/2016 |
| Role |
Principal Investigator |
| Grant Detail |
In this pilot project, we will focus on pain behavioral assays (measuring changes in three different pain modalities) to assess if a novel neuroprotective agent, P7C3-A20, is effective against development of signs of CIPN.
We will test the hypothesis that P7C3-A20 prevents development of signs of CIPN (pain) in rats produced by treatment with paclitaxel, vincristine, oxaliplatin, and bortezomib. These drugs are prototypical members of different classes of anticancer drugs with different mechanisms of anticancer action, but all produce painful peripheral neuropathy. Protection of peripheral pain-sensing neurons from damage will be evaluated using behavioral pain assays (thermal heat, thermal cold and mechanical allodynia) |
| Funding Agency |
NIH/NIGMS |
| Title |
Regulation of Kappa opioid receptor-mediated signaling and peripheral analgesia in female rats |
| Status |
Active |
| Period |
1/2014 - 11/2015 |
| Role |
Principal Investigator |
| Grant Detail |
This is an administrative supplement to extend the study of regulation of kappa opioid receptor (KOR) signaling in peripheral sensory neurons to female rats. The goals of this project are to assess the antinociceptive effects of peripherally-restricted KOR agonists in female rats using behavioral assays of nociception and to assess the cellular signaling of KOR agonists in peripheral sensory neurons derived from female rats. |
Private |
| Funding Agency |
William and Ella Owens Medical Research Foundation |
| Title |
Opioid receptor functional competence in peripheral sensory neurons |
| Status |
Active |
| Period |
1/2013 - 12/2015 |
| Role |
Principal Investigator |
| Grant Detail |
The major goal of this project is to identify the COX and LOX metabolites that regulate the responsiveness of the opioid receptor systems in pain-sensing neurons (nociceptors) |
