Molecular Genetics of Pain
Nausea and Vomiting Mechanisms
Neuronal Injury and Protection
Clinical Trials Program
The Department of Anesthesiology maintains its own industry-sponsored Clinical Trials Program (CTP) with Dr. Jacques E. Chelly, MD, PhD, MBA, Vice Chair of Clinical Research, as Program Director. This program is designed to provide, all the services necessary for faculty members within the department, as both principal investigators and sub-investigators, to start and follow through with a clinical trial.
Inna Belfer, MD, PhD
I am a human geneticist with a primary interest in the relationship between genotypes and complex traits such as human pain, psychiatric diseases, and addictions. My current research focuses on optimizing pain assessment, acute and chronic pain phenotyping, selection of pain candidate genes, and genotyping SNP markers. My primary goal is to identify genetic and non-genetic determinants of human pain conditions such as post-mastectomy chronic pain, with a particular focus in the effect of genotype on the neurobiology of primary afferent neurons in human dorsal root ganglia.
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Nicholas Bircher, MD
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Barbara Brandom, MD
At present I am the Director of the North American MH Registry (NAMHR), now located at UPMC Mercy Hospital. With help from the Malignant Hyperthermia (MH) Association of the United States, we continue to collect data from MH susceptible people and their families and health care providers. As a result, genetic testing for MH susceptibility is performed at UPMC by sequencing 19 exons of the ryanodine receptor type one gene. We encourage researchers across the spectrum to use the NAMHR to investigate MH. The NAMHR is being used to study the clinical presentation of MH in the operating room and chronic muscular symptoms in MH susceptible people.
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Thomas Chalifoux, MD
My primary research interests are medical education and patient safety. Areas of investigation include the use of simulation to assess clinical competency, the role of the electronic health record in clinical decision-making, and transfusion medicine. My clinical expertise is in pediatric and obstetric anesthesiology.
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Feng Dai, PhD
My research focuses on developing statistical methodologies to find genetic variants based on linkage and association between genetic markers and human complex disease. I also collaborate with investigators who have scientific questions in gene mapping, clinical trials, or other biological fields.
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Tomas Drabek, MD
My research carried out at the Safar Center for Resuscitation Research is focused on hemorrhagic shock and resuscitation from both traumatic and non-traumatic cardiac arrest (CA). The main focus is exsanguination CA (ExCA), a relatively unexplored form of CA. Resuscitation of ExCA victims with the conventional cardiopulmonary resuscitation (CPR) technique has a poor prognosis because of a volume-depleted and trauma-disrupted circulatory system. However, in an appropriate setting, many of those injuries would be repairable. We have developed a breakthrough concept of emergency preservation and resuscitation (EPR) that uses cold aortic flush to induce deep hypothermia, thus decreasing metabolic demands to preserve the organs, and buying time for transport and damage-control surgery. Delayed resuscitation is then achieved via cardiopulmonary bypass (CPB). We developed a rat EPR model to elucidate mechanisms associated with ischemia-reperfusion injury, and to test novel therapies. Extended CA durations showed significant regional and temporal differences in neuronal death and neuroinflammation.
Our current work is focused on neuroinflammation-induced reperfusion injury and blocking the deleterious pathways with novel gene-based therapies. We collaborate with the Pittsburgh NMR Center for Biomedical Research at Carnegie Mellon University where cerebral blood flow is assessed with MRI. The use of a rat CPB model also has direct relevance to cardiac anesthesia, including deep hypothermic circulatory arrest.
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Gerald Gebhart, PhD
The principal focus of the laboratory is investigation of the mechanisms of enhanced sensitivity to pain (i.e., hypersensitivity). Because pain arising from internal organs is least well understood among sources of pain, recent research has addressed mechanisms of visceral pain and visceral hypersensitivity, focusing on urinary bladder, colon and pancreas. Experimental approaches include: use of knock out mice to study research questions, in vitro single sensory nerve fiber recording, whole cell patch clamp recording from identified (labeled) sensory neurons, and procedures for quantification or localization of peptides, G protein-coupled receptors, immediate early genes and ion channels that play an important role in pain and hypersensitivity.
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Michael Gold, PhD
Pain continues to be a major health problem with tremendous financial, social and psychological costs. Conservative estimates put the cost of pain to the US economy well into the hundreds of billions of dollars per year as a result of associated medical expenses and lost wages with a significant minority of Americans suffering from persistent or recurrent pain syndromes throughout the most productive years of their lives. Just one pain syndrome, migraine headache, directly impacts 20% of the adult population. Yet, there remain few if any effective therapies devoid of serious side effects that are currently available to treat pain, particularly persistent or recurrent pain associated with syndromes.
The clinical features of a number of pain syndromes serve as the organizing focus of research in the Gold laboratory. These observations include the following: 1) many pain syndromes are unique to a particular part of the body such as the head in migraine, the temporomandibular joint in temporomandibular disorder (TMD), or the colon in inflammatory bowel disease (IBD); 2) many pain syndromes such as migraine, TMD and IBD occur with a greater prevalence, severity and/or duration in women than in men; 3) many pain syndromes are associated with changes in the excitability of primary afferent neurons; 4) there are time dependent changes in the mechanisms underlying pain syndromes; and 5) the type of injury, (i.e., inflammation or nerve injury), are differentially sensitive to therapeutic interventions. These observations led to specific hypotheses that are tested in ongoing studies in the Gold laboratory. These include 1) characterizing the role of Ca2+-modulated K+ (BK) channels in inflammation-induced changes in the excitability of sensory neurons, 2) characterizing the mechanisms of action of serotonin 1D receptor the in regulation of cerobrovascular afferent excitability, 3) characterizing the influence of estrogen on the excitability of spinal and trigeminal ganglion neurons, and 4) characterizing the role of changes in inhibitory receptors, in particular GABA, in injury-induced increases in sensitivity. The ultimate goal of these studies is to identify novel targets for the development of therapeutic interventions for the treatment of pain.
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Ferenc Gyulai, MD
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Charles Horn, PhD
My primary research focus is the neurobiology of nausea and vomiting and more generally the role of gut-brain communication in nutritional homeostasis. Clinically, this is important because many medical treatments and diseases activate the gut-brain axis to elicit nausea and emesis, including cancer chemotherapy agents and analgesics in post-operative recovery. This research involves the use of behavioral, electrophysiological, and functional neuroanatomical work on vomiting species, including humans, musk shrews and ferrets. Musk shrews and ferrets, unlike rodents, such as laboratory rats and mice, have a vomiting response. My laboratory is currently concentrating on defining the neural pathways for the activation of nausea and emesis. I also have collaborative investigations to assess nausea and vomiting in patients and a keen interest in translational research to explore new ways to prevent/control nausea and vomiting based on animal models.
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Gregg Homanics, PhD
My research interests are focused on the mechanism(s) of action of alcohol and anesthetics. My lab is attempting to gain mechanistic insight into the processes of alcohol intoxication and general anesthesia by creating and analyzing genetically altered mice. Specifically, experiments are in progress to genetically dissect the GABA neurotransmitter pathway. GABA receptor knockout, knockin, and overexpressing mice are also helping to elucidate mechanisms of epilepsy, learning and memory, behavior, drug action, and developmental abnormalities as well as serving as models of human genetic disorders, e.g., Angelman Syndrome and essential tremor.
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James W. Ibinson, MD, PhD
The chief focus of my research is the functional magnetic resonance imaging (FMRI) of pain processing. Currently, we are expanding the knowledge of how longer stimulations are processed and investigating the changes in brain activation that accompany long-duration painful stimulation, illustrating those areas of the brain that experience the greatest signal changes due to accommodation. In addition, projects are in place to research the connection between genetics and brain activation, as well as exploring the impact that treatment of neuropathic pain can have on the brain's activation pattern. As a practicing anesthesiologist, I believe that the role of the physician-scientist is to translate the tools, techniques, and treatments derived in the basic science laboratories to the clinical realm. Thus, the overall goal of these three projects is to further our understanding of chronic pain and impact future treatment strategies and success.
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Eric Kelley, PhD
Dr. Kelley’s research centers on the role of oxidative stress in vasculature inflammation with a primary focus on the modulation of endothelial homeostasis by xanthine oxidase (XO)-derived ROS. Such ROS production, when it occurs in the vascular compartment, can impact vessel function by modulation of redox-dependent cell signaling reactions or by the reduction of •NO bioavailability due to its direct reaction with superoxide. An expanding number of animal models and clinical studies affirm a key role for XO in tissue pathology where inhibition of XO activity attenuates symptoms of vascular disease. However, recently reported studies demonstrate under severe hypoxia, XO may function as a nitrite reductase and thus assume a protective role by serving as a source of vasoactive nitric oxide (NO). Therefore, in order to develop novel treatment strategies, Dr. Kelley’s efforts are globally targeted to develop a more comprehensive understanding of XO-derived ROS/RNS in vascular inflammatory processes.
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William Lariviere, PhD
Marked variability is observed in clinical pain reports and in sensitivity to experimental stimuli in people and animals. Genetic factors significantly contribute to this variability, but we are only in the initial stages of identifying the responsible genetic mechanisms. In my lab, we are using rodent strain differences to study genomic covariance with sensitivity to a number of genetically fundamental types of pain. These include spontaneous pain behaviors due to inflammation and the subsequent prolonged hypersensitivity that is of greater relevance to clinical pain than the vast majority of experimental pain traits mapped so far. The methods we use include genetic correlation analysis with standard inbred strains of mice and whole-genome quantitative trait locus (QTL) genetic mapping of recombinant inbred mice. Biostatistical analyses of archival genomic, phenomic and transcriptomic data are then performed to expand the analysis to a systems genetics level. These methods are complemented by candidate gene testing with neuropharmacological and other studies to determine the responsible genes underlying the pain traits, analgesia traits including stress-induced endogenous pain suppression, and sensitivity to treatment side effects. This research will identify novel genes involved in the traits and provide novel therapeutic targets.
A second area of interest is in the interactions between stress and pain systems that modulate pain sensitivity and may lead to increased susceptibility to chronic pain. Although acute stress usually decreases pain sensitivity, prolonged stress is considered to lead to increased pain sensitivity and greater susceptibility to chronic pain. We are currently concentrating on the effects of corticotropin-releasing factor (CRF) receptor ligands, knockout of CRF receptor subtypes, and on the specificity and mechanisms of the effects of hypophysectomy, which can dramatically alter pain sensitivity in rodents and in advanced cancer pain patients.
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William McIvor, MD
I am interested in developing and implementing simulation education for medical students, resident-physicians and practicing physicians. Methods and impact of the education are of particular interest.
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Jerome Parness, MD, PhD
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Tetsuro Sakai, MD, PhD
My primary interest in basic research is elucidation of the mechanism of stem cell derived neuronal protection (Mentor: Yan Xu, PhD). Our main hypothesis is that transplanted stem cells in the brain achieve neuronal protection through extracellular signaling pathways. This “by-stander” protection mechanism of stem cells is a novel concept. Using an in vitro co-culture system and protein array technology, we have identified several candidate proteins potentially responsible for protection of rat fetal neuronal cells from hypoxic damage, notably TIMP-1 and TIMP-2. It is my goal to identify and confirm such key protein(s).
As a member of the hepatic transplant anesthesiology team, I am deeply interested in intraoperative management of liver / small bowel / multiviceral transplant patients. My current main goal is to identify the risk factors of intraoperative pulmonary thromboembolism and work towards its prevention during liver transplantation.
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Joseph Samosky, PhD
I enjoy building interdisciplinary teams and creating bridges between medicine and engineering, helping to develop solutions at the interface of clinical medicine, technology, and education. I work collaboratively with clinicians, engineers, designers, instructors, and students to develop new techniques and technologies for medical simulation and medical devices by defining and translating clinical needs and instructional goals into new system features and specific design ideas for enabling technologies. The ultimate goal is better medical training with reduced risk and discomfort to patients and better outcomes for all.
Our research group, the Simulation and Medical Technology R&D Center, focuses on the user-centric design and engineering of real-time interactive systems, including sensor-rich simulation systems to enhance healthcare training, and smart medical devices with embedded sensing, information display, and autonomous responses. I am especially interested in ways that sensor-rich medical simulators can serve as sophisticated performance measurement tools and intelligent tutors with innovative feedback techniques, helping to quantify and improve performance across scales from the individual trainee to entire integrated patient care systems.
Specific areas of research include the design and systems engineering of integrated computer, electronic and mechatronic systems, embedded intelligent systems, sensors and actuators, biomimetic materials and advanced 3D fabrication techniques, anatomic and physiologic modeling methods, advanced perceptual display systems including augmented and hybrid reality interfaces, tangible interfaces, interaction design, and learner-adaptive and intelligent systems.
My previous research and development efforts include serving as systems engineer and co-architect of COMETS, the Combat Medic Training System, an autonomous, whole-body humanoid robotic simulator that enables trauma training and assessment in field environments. Other research has included the development of a simulator of arthroscopic knee surgery, a 3D visualization system for medical images, and methods for the noninvasive MRI-based measurement of the mechanical properties of articular cartilage.
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Pei Tang, PhD
My research focuses on the molecular mechanisms of general anesthesia. Using a hydrate biophysical approach, we have been working on two major projects. The first one is to determine high-resolution structures of neurotransmitter-gated receptor channels, such as neuronal nicotinic acetylcholine receptors. These receptors are not only the targets for general anesthetics, but also for CNS therapeutics. Since the current structural information of these receptors is still very limited, our research will provide valuable structural bases for searching for drug binding sites. The second project aims to understand how low affinity drugs, including inhaled and intravenous general anesthetics, modulate protein motions that ultimately have impact on protein functions. Through our experiments and computations, we are testing our new hypothesis: the lock and key relationship does not accurately describe the action of low affinity drugs on proteins, the modulation on protein motions is the mechanistic underpinnings of action of general anesthetics and other low affinity drugs.
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Margaret Tarpey, MD
My research is centered on the interplay of oxidants with nitric oxide in vascular dysfunction, including hypertension and atherosclerosis. I am particularly interested in the involvement of xanthine oxidase in elevated steady state production of superoxide and hydrogen peroxide in diseased vascular tissue. Development of site-directed antioxidants to ameliorate local production of oxidants is also a critical focus of my research endeavors.
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Brian Williams, MD, MBA
Currently, I am pursuing translational bench research at the Pittsburgh Center for Pain Research (PCPR) to develop multimodal single-injection and continuous infusion perineural analgesia, with the specific goals of maximizing the duration of sensory analgesia while minimizing the duration of motor and proprioceptive block. The public health objectives are to render single-injection nerve block techniques both more efficacious for patients and more accessible for anesthesiologists to administer quickly. My past research interests included the restructuring of anesthesia care processes to render regional anesthesia as the primary anesthetic technique (spinal, single-injection peripheral nerve block, continuous nerve block), while relegating general endotracheal anesthesia to the "backup" plan. My work has addressed health care economics and hospital staff workload (in retrospective study), as well as patient-reported outcomes via validated survey instruments (in prospective study).
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Yan Xu, PhD
Current research efforts are directed at combining new innovations in powerful gene therapy and stem-cell therapy with state-of-the-art MRI techniques. Our laboratory has developed a clinically relevant cardiac arrest and resuscitation model that is fully compatible with noninvasive magnetic resonance spectroscopy and imaging techniques, thus permitting pharmacological intervention and long-term outcome to be investigated. New gene therapy strategies are being developed to target a special event called reperfusion injury after cardiac arrest and resuscitation. Recently, our group has combined gene therapy with stem cell therapy using a non-controversial source of stem cells, in an effort to stop and reverse neuronal loss and to rebuild neuronal circuitry after reperfusion from prolonged cardiac arrest or stroke.
Our group is one of the leading groups in the world to combine the high-resolution and solid-state NMR techniques to solve membrane protein structures at the atomic resolution. The current focus is on the transmembrane domain structures of the human glycine receptor (GlyR), the primary inhibitory receptor in the spinal cord and the brain stem which is responsible for a wide range of neurological diseases including the startle disease (hyperekplexia), epilepsy, and Parkinson's disease. The long-term goal is to provide the structural basis for novel design of drugs that are disease specific and devoid of side effects.
We are also studying low-affinity drug interaction with membrane proteins. Experimental and theoretical approaches are combined to study how low affinity neurological agents, such as alcohol and general anesthetics exert their effects on the central nervous system at the molecular level. The goal is to shed new light on the great unsolved mystery of modern medicine: the molecular mechanisms of general anesthesia.
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Charles Yang, MD
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Erin Young, MD
My primary interest lies in the understanding of gene x environment interactions on pain outcomes, with a particular focus on stress and injury/inflammation as environmental factors. Genetic factors have been shown to contribute significantly to variability in the response to painful stimuli. We are beginning to unravel the individual gene candidates and the families of genes that contribute to differences in pain responses. Using genetic correlation analysis with standard inbred strains of mice in addition to whole-genome quantitative trait locus (WTL) mapping with genetic reference populations as our most powerful tools, we are able to explore the genetic contribution to both somatic and visceral pain behaviors. Stress and inflammation can both modulate pain responses to various stimuli, and it is likely that they are genetically independent from pain. However, little is known about the interactions between specific genes and environmental factors that are known to influence pain. The goal is to further understand the mechanisms underlying pain and to use this knowledge to identify novel therapeutic targets to reduce pain and suffering in clinical populations.
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Li-Ming Zhang, MD
It is well known that mechanical ventilation may produce an iatrogenic condition referred to as ventilator-induced lung injury (VILI). VILI can contribute to mortality in patients with acute lung injury (ALI). Patients vary greatly in VILI sensitivity suggesting that genetic determinants may control individual susceptibility. Our research lab is currently focusing on functional genomics of ventilator-induced lung injury. We adopted a Genome-wide association study (GWAS) technique to interrogate the entire genome simultaneously to detect loci linked to a phenotype that reside in previously unsuspected genes and/or regions in 40 inbred strains of mice exposed to VILI induced by high tidal volume ventilation. Our initial GWAS analysis identified 18 genes with significant SNP linkage [–log (P) = 6.0 to 9.5]. Of these, 4 genes (Adcy8, Asap1, Ndrg1 and Wisp1) were located in a single region (64.1 – 66.7 Mbp) on chromosome 15. Our goals are to identify these target candidate genes by pulmonary functional assessment and provide novel insights into the underlying pathogenesis of VILI and ultimately help translate animal studies to patient care to minimize the detrimental effects of using mechanical ventilation in human subjects and to guide novel therapeutic interventions to ALI.
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