Research

Department of Pharmacology

Pharmacology Research

Faculty of the Department of Pharmacology participate in several interdisciplinary graduate programs, including the Cellular and Molecular Pharmacology and Physiology Graduate Program (CMPP), the Cell and Molecular Biology Program (CMB) and the Biomedical Engineering Program (BME).

For more information on labs, please visit the associated lab page or contact the PI. 

Research Labs

Agarwal Lab

  • Regulation of ion channels and cell signaling by autonomic nervous system in mammalian heart.
  • The focus of our lab is to study the regulation of cardiac function by autonomic nervous system in health and disease. The sympathetic and parasympathetic branches of autonomic nervous system act in concert to maintain autonomic tone and control the activity of ion channels in the heart. This regulation of electrical activity is accomplished by signaling via production of a common second messenger cyclic adenosine monophosphate (cAMP). Maintaining specificity of responses following the activation of autonomic pathways is believed to be accomplished by compartmentation of cAMP signaling into highly localized and distinct subcellular microdomains. However, what constitutes these compartments is unclear. Dysregulation of spatiotemporal gradients of cAMP can disrupt localized signaling and contribute to development of abnormal heart rhythms called arrhythmias. Cardiac arrhythmias are associated with life-threatening medical emergencies and sudden cardiac death, the leading cause of death in humans. To elucidate the complex subcellular mechanisms that are important for cell signaling and ion channel regulation in cardiac myocytes, we utilize a variety of biophysical techniques. These include electrophysiological measurements such as whole cell patch clamp recordings as well as advanced imaging techniques including fluorescence resonance energy transfer (FRET), fluorescence recovery after photobleaching (FRAP) and confocal microscopy. Our long-term goal is to identify the causes for impaired subcellular signaling and develop novel therapeutic remedies for newly identified targets in disease state.
  • Shailesh Agarwal. Ph.D. profile

Baker Lab

  • We use single molecule techniques (TIR fluorescence microscopy and optical traps) to study how mechanoenzymes like actin and myosin transfer chemical free energy to mechanical work and inversely how they convert mechanical signals into chemical responses. We are particularly interested in understanding how the mechanochemical behaviors of single molecules scale up to the mechanochemical behaviors of bulk cellular systems. We use mathematical and computer models to integrate our multi-scale experimental studies, developing self-consistent descriptions of muscle contraction, intracellular transport, and mechanical signal transduction.
  • Josh Baker, Ph.D. profile

D. Burkin Lab

  • Translational research identifying novel therapies for children with muscular dystrophy. Role of extracellular matrix and integrin signaling in muscle development and disease.
  • The primary goal of my research is to understand the role integrin receptors and the extracellular matrix play in neuromuscular development and disease. Using transgenic and knockout mice we have shown that the α7β1 integrin is a major modifier of disease progression in several muscular dystrophies including Duchenne Muscular Dystrophy (DMD) and Merosin-Deficient Congenital Muscular Dystrophy type 1A (MDC1A). These studies support the idea that the α7β1 integrin is a drug target for the treatment of these and potentially other fatal muscle diseases. Using a novel muscle-based assay and high throughput drug discovery, we have recently identified that laminin-111 protein can increase α7 integrin protein in mouse and human muscle cells. We have demonstrated laminin-111 protein therapy can improve muscle repair after damage and prevent muscle disease progression in mouse models of DMD and MDC1A. In addition, we have identified several integrin-enhancing small molecules that may be useful in the treatment of muscle disease and serve as molecular probes to identify and dissect signaling pathways regulated by the α7β1 integrin in normal and diseased muscle.
  • Dean Burkin, Ph.D. profile

H. Burkin Lab

  • Research in my laboratory is focused on understanding the molecular mechanisms that promote uterine contraction and the onset of labor. Preterm birth is the leading cause of neonatal morbidity and mortality in the developed world and the long-term goal is to develop new therapies to promote uterine quiescence and allow a greater proportion of infants to be carried to term. Identification of new pharmacological agents to reduce uterine contraction would reduce preterm birth rates, reduce perinatal health disparities, and improve pregnancy outcomes, all of which have been identified as high priority research problems by the National Institutes of Health. My research has primarily focused on three related projects: the role of matrix metalloproteinases (MMPs) in the regulation of uterine contraction and birth timing, changes in uterine smooth muscle that precipitate labor caused by mechanical strain, and development of a novel 3D bio-printed model of human uterine tissue.
  • Heather Burkin, Ph.D. profile

Buxton Lab

  • The broad interests of our laboratory are those of receptor-signal transduction in mammalian systems. We approach our interests with modern biochemical and molecular methods that include intracellular imaging of events such as calcium release. One of our principal interests, for example, is the problem of premature delivery of babies. The signals that initiate contraction of the uterus at the time of labor are not known. We have recently described the contractile actions of adenyl purines on the smooth muscle of guinea pig uterus and find that the receptor that mediates the contraction of the tissue changes its coupling mechanism significantly during pregnancy in a fashion consistent with a role for these compounds in human parturition. The problem of premature delivery is a devastating human problem that takes its toll both in lives and dollars. We hope to contribute to an understanding of the onset of labor in order to help eliminate the problem of premature delivery.
  • Iain Buxton, Pharm.D. profile

Craviso Lab

  • Interaction of electromagnetic fields with excitable cells; exploring the potential for nanosecond duration electric pulses of high intensity as a new, bioelectric approach for stimulating neural cells.
  • Within the past decade, deep brain stimulation that delivers microsecond duration electric pulses to specific brain regions via surgically implanted electrodes has become an established treatment for movement disorders (e.g., Parkinson's disease, tremor and dystonia) in patients who either do not respond to drug treatment or else experience unacceptable drug side effects. Other potential clinical applications of deep brain stimulation include treatment of epilepsy, pain and neurological disorders such as depression. My research builds on the growing clinical acceptance of electric stimulation for neuromodulation by focusing on a new type of electric stimulus, high intensity (> 1 megavolt-per-meter), nanosecond duration electric pulses, as an emerging technology for altering neural cell excitability. In a highly interdisciplinary collaborative effort, I have been exploring the effectiveness of nanoelectropulses less than 10 ns in duration for evoking neurosecretion. The hope is that the research will be critical to the future development of an electrostimulation approach that is less invasive (does not require surgical implantation of electrodes) than the one currently used for neuromodulation, and that it will also result in new strategies for modulating the activity of other types of excitable cells.
  • Gale Craviso, Ph.D. profile

Cremo Lab

  • Regulation of smooth muscle contraction.
  • Solution kinetics of myosin-actin interactions.
  • Single molecule kinetics of myosin-actin interactions.
  • Single molecule interactions of myosin light chain kinase with cytoskeletal proteins.
  • Christine Cremo, Ph.D. profile

Dagda Lab

  • The Dagda Lab is a mitochondrial biology-oriented research group located at the University of Nevada, Reno School of Medicine that currently spearheads basic and translational research projects on Parkinson's disease, Alzheimer's disease, and Amyotrophic Lateral Sclerosis.
  • Regulation of mitochondrial biology and bioenergetics by serine/threonine kinases and phosphatases in neurons and in cardiac cells; new signaling pathways that promote synaptic connectivity; development of alternative therapies to reverse mitochondrial dysfunction in age-related brain diseases.
  • Ruben Dagda, Ph.D. profile

Earley Lab

  • My lab is focused on understanding the functional significance of the transient receptor potential (TRP) superfamily of cation channels in the cerebral vasculature and other organ systems. The mammalian TRP superfamily is composed of 28 distinct gene products assigned to six subfamilies based on sequence homology. TRP channels act as fundamental sensors of the environment at the cellular level and mediate appropriate responses to stimuli such as light, pressure, temperature, changes in osmolarity, and certain chemical agonists. Although prominent in sensory neurons, multiple TRP channels are present in most types of cells. We are primarily interested in learning how TRP channels are involved in smooth muscle excitability and contractility, endothelium-dependent vasodilation, and cellular proliferation during pathophysiological conditions. We employ a broad range of modern experimental approaches and techniques. For example, high-speed confocal Ca2+ imaging in conjunction with mice expressing genetically-encoded Ca2+ indicators in the endothelium are used to study transient, localized Ca2+ signaling in intact arteries and isolated cells. Ion channel regulation is studied using both conventional patch clamp electrophysiology and total internal reflection fluorescent microscopy (TIRFM). Tissue-specific gene knockout and delivery of siRNA to intact cerebral arteries are routinely used to disrupt gene expression, and in combination with pressure myography, ratiometric Ca2+ imaging, and intracellular microelectrode electrophysiology, to examine the consequences of protein downregulation on arterial function. Live-cell imaging techniques, including TIRFM and fluorescence recovery after photobleaching (FRAP), are used to study ion channel trafficking. Experiments are typically performed under physiological conditions using intact resistance arteries or acutely isolated cells from these vessels.
  • Scott Earley, Ph.D. profile

Feng Earley Lab

  • Our laboratory investigates neural circuitry mechanisms of cardiovascular metabolic diseases including hypertension, diabetes, non-alcoholic fatty liver diseases and Alzheimer's diseases. We are currently interested in the physiological and pathophysiological role of the renin-angiotensin system (RAS), (pro)renin receptor (PRR) and prorenin as a novel pathway for brain RAS. Briefly, we are investigating the importance of brain RAS in neurons, astrocyte, and microglial cells in mediating angiotensin II formation, and the neural circuits from the forebrain subfornical organ (SFO) and the paraventricular nucleus of hypothalamus (PVN) to the brainstem autonomic regulatory centers.
  • Yumei Feng Earley, M.D. Ph.D. profile

Harvey Lab

  • Sudden cardiac death kills as many as 300,000 Americans every year, and in most cases the ultimate demise of the individual is due to the abrupt onset of abnormal electrical activity or cardiac arrhythmia. Even though the incidence of sudden cardiac death is often associated with some sort of preexisting condition, a significant number of victims have no apparent underlying cardiovascular disease. The critical, yet unanswered question is what triggers fatal arrhythmias in these individuals? Although the mechanisms responsible remain largely unknown, there is substantial evidence that heart-brain interactions involving the autonomic nervous system play a critical role in many cases. Our working hypothesis is that dynamic interactions between the sympathetic and parasympathetic branches of the autonomic nervous system trigger abnormal electrical responses that can lead to the generation of life threatening ventricular arrhythmias. We believe that these abnormal responses are due to complex subcellular signaling mechanisms that affect the activity of a number of different ion channels in the heart. To test our hypothesis, we are using a systems biology approach that combines computational modeling with a variety of powerful experimental techniques. These include single cell recording of membrane currents and action potentials as well as live cell imaging of subcellular signaling responses using fluorescence resonance energy transfer (FRET) based biosensors. The ultimate goal is to identify the conditions under which imbalances in autonomic tone are likely to trigger ventricular arrhythmias in order that they might be prevented.
  • Robert Harvey, Ph.D. profile

Jones Lab

  • Facioscapulohumeral muscular dystrophy (FSHD) is the most prevalent muscular dystrophy that affects males and females, children and adults and affects ~1 million individuals worldwide. Currently there is no cure or ameliorative treatment. Our goal is to help change this through a multi-pronged approach to relieve key bottlenecks in the therapeutic pathway by 1) creating much-needed tools for FSHD preclinical testing (e.g., FSHD-like mouse models and large animal models), 2) developing novel FSHD-specific therapeutics (e.g., CRISPR-inhibition gene therapy and small molecule drugs targeting DUX4 expression), 3) identifying circulating biomarkers to aid in clinical trials, and 4) to make FSHD diagnostics affordable and accessible to the worldwide FSHD community.
  • Drs. Peter and Takako Jones function as Co-PIs, combining expertise in epigenetic gene regulation, biochemistry and chromatin biology with expertise in cell biology, developmental biology and molecular biology to address important questions in FSHD. Overall, we investigate the epigenetic dysregulation leading to pathogenic gene expression in FSHD to understand disease mechanisms, identify therapeutic targets, design novel therapies, and improve FSHD diagnostics.
  • Peter Jones, Ph.D. profile
  • Takako Jones, Ph.D. profile

Leblanc Lab

  • My laboratory is interested in determining the properties and function of ion channels and electrogenic ion transport systems in the control of vascular tone and cardiac excitation-contraction coupling. Using a wide array of electrophysiological (classical intracellular recording and patch clamp techniques), quantitative fluorescence imaging (Indo-1, Fura-2 and Fluo-4 epifluorescence and total internal reflection fluorescence microscopy or TIRFM) and biochemical (immunocytochemistry, Western Blot, enzyme assays) and molecular biological (cloning and expression of ion channel proteins) techniques, our efforts have mainly focused on investigating the biophysical properties and signaling pathways involved in the regulation of Ca2+-activated Cl- channels (CaCCs) in vascular smooth muscle cells. Recently, three independent groups of investigators have identified Tmem16a as the gene encoding for CaCCs in vascular myocytes. We are currently exploring how the protein encoded by this gene called TMEM16A or Anoctamin-1 is regulated by phosphorylation, and establish the identity of the kinases and phosphatases that are responsible for this process. Finally we recently found that the activity of CaCCs and expression of TMEM16A are up regulated in pulmonary artery smooth muscle cells from animal models of pulmonary hypertension and have embarked on studies examining the effect this increase activity has in the enhanced vasoconstriction and pulmonary arterial wall remodeling that are known to occur in human pulmonary arterial hypertension. 
  • Normand Leblanc, Ph.D. profile

Liebman Lab

  • Certain neurodegenerative diseases, such as ‘mad cow' disease, are transmitted in an unusual way-- so unusual that it challenges the central dogma. Indeed, the infectious agent for these diseases appears to be the PrP protein without any nucleic acid. Infectivity depends upon the shape into which the PrP protein is folded: when some PrP is in its disease-causing (‘prion') conformation, it converts normal PrP into that form too. In addition, prion-like aggregates of A, α-synuclein, TDP-43, and huntingtin are respectively associated with Alzheimer's (AD), Parkinson's, amyotrophic lateral sclerosis (ALS)/ frontotemporal dementia (FTD) and Huntington's dis-eases.
  • Curiously, several genetic traits in yeast are propagated by this unusual ‘protein only' mechanism, and the term prion has been expanded to include them. We have studied yeast prions extensively to elucidate the factors that influence prion appearance and inheritance and to identify new prions. We are now using our expertise with yeast prions to focus on the genesis and toxicity of human prion-like disease aggregates. Results obtained in yeast will then be tested in flies, primary cortical neurons and mice, by collaborators.
  • We previously established that individual yeast prions can form self-seeding aggregates with more than one conformation ("variants or strains") associated with distinct properties. Prion variants self-propagate by attract-ing their soluble isoforms to join them and adopt their variant-specific structure. Likewise, PrP, A, α-synuclein, huntingtin, tau and TDP-43 have each been reported to form distinct aggregate phenotypes that are associated with different disease characteristics. We are now using yeast to isolate and characterize variants of TDP-43. This will definitively demonstrate the existence of heritableTDP-43 variants and will open the door to the study of patient variants in yeast, thereby facilitating development of variant specific treatments.
  • Since human prion-like disease proteins aggregate and are toxic when expressed in yeast, a powerful ap-proach to find therapeutic targets has been to identify toxicity modifiers. Some such modifiers are homologs of new or previously known human disease risk factors!! Thus studies in yeast, with its powerful experi-mental toolbox, are relevant to human disease.
  • As previous modifier screens were not exhaustive we have now identified several new modifier genes that we are exploring. We are also using two new approaches to identify toxicity modifiers: 1) transposon mutagenesis and deep sequencing to quickly identify all genes that become essential in the presence of the human disease proteins and 2) direct selection against aggregation (yTRAP) to uncover additional modifier loci, as well as intra-genic dominant mutations that reduce toxicity. We are also starting similar modifier screens on another ALS as-sociated gene, CREST that we have now expressed and characterized in yeast.
  • Another focus of the lab is to determine how TDP-43 is associated with toxicity. Several studies find that TDP-43 alters mitochondrial function. We have found that TDP-43 is much more toxic when yeast is grown in non-fermentable media requiring respiration than when grown on fermentable carbon sources. However, we also found that TDP-43 remains toxic in the absence of respiration. Thus, there is a TDP-43 toxicity target in yeast distinct from respiration and respiration is not required for this toxicity. One possibility is that the free radical ox-ygen species produced by respiration activate TDP-43 to become more toxic, or make TDP-43 targets more vulnerable. Indeed, we found that hydrogen peroxide increases the toxicity of TDP-43.
  • Susan Liebman, Ph.D. profile

Singer Lab

  • Sudden cardiac death kills as many as 300,000 Americans every year, and in most cases the ultimate demise of the individual is due to the abrupt onset of abnormal electrical activity or cardiac arrhythmia. Even though the incidence of sudden cardiac death is often associated with some sort of preexisting condition, a significant number of victims have no apparent underlying cardiovascular disease. The critical, yet unanswered, question is what triggers fatal arrhythmias in these individuals? Although the mechanisms responsible remain largely unknown, there is substantial evidence that heart-brain interactions involving the autonomic nervous system play a critical role in many cases. Our working hypothesis is that dynamic interactions between the sympathetic and parasympathetic branches of the autonomic nervous system trigger abnormal electrical responses that can lead to the generation of life threatening ventricular arrhythmias. We believe that these abnormal responses are due to complex subcellular signaling mechanisms that affect the activity of a number of different ion channels in the heart. To test our hypothesis, we are using a systems biology approach that combines computational modeling with a variety of powerful experimental techniques. These include single cell recording of membrane currents and action potentials as well as live cell imaging of subcellular signaling responses using fluorescence resonance energy transfer (FRET) based biosensors. The ultimate goal is to identify the conditions under which imbalances in autonomic tone are likely to trigger ventricular arrhythmias in order that they might be prevented.
  • The long-term goal of my laboratory is to understand the molecular mechanisms regulating phenotypic plasticity in smooth muscle cells. Phenotypic plasticity is a phenomenon by which mature contractile smooth muscle cells reversibly switch to an immature synthetic phenotype, which can result in the production of inflammatory mediators coupled with changes in cell numbers and mass. Our laboratory was one of the first to describe miRNA expression in human airway smooth muscle cells and have identified miR-25 as a target of phenotypic plasticity in this cell type. We are currently investigating the mechanisms by which miR-25 and other miRNAs regulate airway smooth muscle phenotype in culture by studying inflammatory, proliferative and contractile functions of airway smooth muscle cells. We are also developing a transgenic animal model of miR-25 expression to study the role of this miRNA on lung function in an animal model of allergic asthma.
  • We are currently furthering our study of miRNA in other smooth muscle cell types. Our laboratory collaborates with the Myometrial Function Group to explore the regulation of miRNA in human uterine smooth muscle function. The goal of this work is to identify gene-silencing pathways leading to the onset of pre-term labor. We are examining miR-25 function is vascular smooth muscle cells to determine whether miR-25 expression affects smooth muscle phenotypes relevant to cardiovascular disease.
  • Cherie Singer, Ph.D. profile