2012-2013 PROJECTS AVAILABLE FOR ANESTHESIA INTEREST GROUP MEMBERS & MEDICAL STUDENT
SCHOLARLY PROJECTS:
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Genetics of Post-Mastectomy Pain
Inna Belfer, M.D., Ph.D., Associate Professor of Anesthesiology
Molecular Epidemiology of Pain Program
Persistent pain following breast cancer surgery is highly disabling and is a significant
clinical problem due to limited treatments. Up to 47% of patients report pain after
surgery, of which 13% is severe, and up to 40% moderate. Little is known about risk
factors contributing to pain chronicity and their interaction that affects inter-individual
variability in pain. This study will identify genetic & environmental (demographic,
surgical, psychological) factors associated with persistent pain phenotypes. We collect
comprehensive data on 2000 women who had standard therapies for breast cancer at
Magee-Women’s Hospital. We perform Quantitative Sensory Testing in a subsample of
these subjects. Genetic data will be collected using DNA extracted from frozen blood.
Clinical: Interviewing patients for pain and pain-related traits assessment using webbased surveys; quantitative sensory testing using standard protocols for static and
dynamic stimulation.
Genetics of Labor Pain and Analgesia
Inna Belfer, M.D., Ph.D., Associate Professor of Anesthesiology
Molecular Epidemiology of Pain Program
Significant pain is reported in up to 50% of pregnant women in the months prior to
delivery, and in 30% of women months to years after delivery. Attempts to explain this
variability with physical markers have thus far failed. This study seeks to understand
the genetic and environmental (clinical, medical, demographic, psychosocial) factors
associated with the incidence of persistent pain during and after childbirth. Prospective
design, multiple time points for follow-up and comprehensive approach to data
collection makes this project challenging. The ultimate aim of current pilot and future
larger-scale studies is to predict which women are at risk for poor labor analgesia and
chronic post-partum pain development. This will hopefully lead to more
personalized peri-partum pain management.
Student’s input will have tremendous value and will help to identify the unique
individual “fingerprint” that may predispose women to chronic pain.
Clinical: Interviewing patients for pain assessment and quantitative sensory testing;
Laboratory: DNA extraction and genotyping of pain candidate genes.
Student can participate in either or both components.
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The North American Malignant Hyperthermia Registry
Barbara W. Brandom, M.D., Professor of Anesthesiology
and Jerome Parness, M.D., PhD., Professor of Anesthesiology
Dr. Brandom’s group maintains the North American Malignant Hyperthermia (MH)
Registry, which now contributes to the Global Rare Disease Registry. Research will
focus on measures of muscular function that could document the sub-clinical chronic
myopathy that is one of the manifestations of some mutations in the ryanodine receptor
gene. Studies into the genetics of MH susceptibility and the phenotype of MH
susceptibility are ongoing.
Trainees will participate in research projects involving de-identified data already
acquired by the North American Malignant Hyperthermia Registry (over 4,000 cases).
They will develop and execute projects involving patients diagnosed as malignant
hyperthermia (MH) susceptible or MH negative, and may prepare data for analysis,
perform descriptive statistical analysis, and present the data at a research meeting.
Preliminary Studies for Whole Genome Association Study (WGAS) in Acute
Perioperative Pain
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Jacques E. Chelly, M.D., Ph.D., M.B.A., Professor of Anesthesiology and Orthopedic
Surgery, Vice Chair of Clinical Research
This preliminary, developmental, prospective genome-wide association study will
explore genetic mechanisms responsible for variation in pain perception. The study will
attempt to correlate markers on genes & single nucleotide polymorphisms w/ patient
phenotypes (quantitative sensory/motor testing, psychometric questionnaires & other
clinical variables). The aim is to devise a method for defining a pain phenotype
sensitive enough to detect differences in genotype between subjects who undergo a
standard surgical procedure. Subjects undergoing total knee arthroplasty will be
genotyped for genes associated with pain & single nucleotide polymorphisms (SNPs),
and phenotyped in the perioperative period. Fluids will be collected for biomarkers of
inflammation analysis using multiplex immunoassay.
Trainees will be responsible for all clinical research duties including but not limited to
enrolling subjects, phenotyping using quantitive sensory/motor testing, administering
psychometric questionnaires, processing of biological specimens, and data analysis.
Laboratory interest can also be accommodated to include DNA extraction/genotyping
and multiplex immunoassay.
Inflammation-induced Changes in the Actions of Local Anesthetics
Michael S. Gold, Ph.D., Professor of Anesthesiology
Regional nerve blocks are now a standard component of post-operative pain
management. However, we have recently obtained data indicating that there are a
number of conditions in which there is not only a loss of local anesthetic potency, but
where the use of local anesthetics may even have deleterious consequences. The goal
of this project is to determine the mechanisms underlying the loss of local anesthetic
potency as well as an increase in local anesthetic toxicity.
Will vary depending on student interests but can involve anything between
behavioral pharmacology using pre-clinical models, to biochemical and/or physiological
analysis is isolated tissues.
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Injury-induced Changes in the Regulation of Intracellular Ca2+
Michael S. Gold, Ph.D., Professor of Anesthesiology
Ca2+ is plays a critical role in mediating an array of physiological as well as
pathophysiological processes in peripheral neurons. We have evidence that changes
in the regulation of intracellular Ca2+ contribute to the manifestation of persistent pain
states. Interestingly, the type of tissue injury appears to influence the specific pattern of
changes in intracellular Ca2+, suggesting that the pattern of changes may also
contribute to the unique qualities of the pain state specific to particular types of injury.
To tease out the basis for these differences as well as the underlying mechanisms, we
have been studying changes in the regulation of intracellular Ca2+ in models of
persistent inflammation and more recently, nerve injury.
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Trainees will participate in research projects involving the function and biochemical
analysis of Ca2+ regulation in sensory neurons from rat and human donors.
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Role of GABAa Receptors in Ethanol Action
Gregg E. Homanics, Ph.D., Professor of Anesthesiology
Research in Dr. Homanics laboratory applies genetic dissection of putative
molecular targets of ethanol to explain the neurophysiologic basis of ethanol action.
Knockin mice with alterations in specific GABAA-R and glycine receptor subunit genes
will be created, characterized, and tested. These novel mice will be analyzed with tests
spanning molecular, cellular, and behavioral levels. Such a multi-level approach allows
a determination of the relevance of a specific drug target (receptor) as a mediator of a
specific phenotype (e.g., motor ataxia).
Techniques student may learn: Molecular biology: recombinant DNA procedures,
PCR, Southern blotting, vector construction. Cell culture: embryonic stem cell culture,
electroporation, drug selection of clonal cell lines. Animal analysis: whole animal drug
responses, behavioral characterization.
The Effect of Neuroinflammation on Neurologic Outcome after Deep Hypothermic
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Circulatory Arrest in Rats
Patrick M. Kochanek, M.D. Professor of Critical Care Medicine & Director of the Safar
Center for Resuscitation Research
Tomas Drabek, M.D., Assistant Professor of Anesthesiology
Cardiopulmonary bypass (CPB) & deep hypothermic circulatory arrest (DHCA) are
used to provide a bloodless field during cardiac surgery while minimizing cerebral
ischemia. However, neurological complications remain a significant concern. More
subtle neurological deficits could be triggered by inflammatory reaction in the glia. We
have developed a rat CPB model to elucidate mechanisms associated with ischemiareperfusion injury after DHCA, and to test novel therapies. We showed that deep
hypothermia attenuates microglial proliferation independent of neuronal death after
DHCA, and improves neurologic outcome. These findings underscore the role of
neuroinflammation. In current studies, we are selectively
targeting neuroinflammation to improve outcome.
The role of the student would be assisting during rodent experiments involving
cardiopulmonary bypass, assessment of neurobehavioral outcome after deep
hypothermic circulatory arrest, evaluation of neurohistochemistry, and magnetic
resonance imaging (in cooperation with Carnegie Mellon University).
The Genetics of Pain in Rodents and Humans
William R. Lariviere, Ph.D., Assistant Professor of Anesthesiology
Dr. Lariviere’s lab is determining the genetics of variability in several pain traits in mice,
including mechanical sensitivity, inflammatory nociception and hypersensitivity, and
neuropathic hypersensitivity. Advanced mapping populations of mice, biostatistics and
genome-wide and tissue-specific expression data are used to understand which
genetic mechanisms are involved in the traits. Novel genetic targets are then tested
with molecular and behavioral pharmacology methods. High priority targets are tested
for genetic association in human cohorts. Dr. Lariviere’s lab has performed
psychophysical testing of healthy human subjects’ sensitivity to capsaicin, the pungent
substance of hot peppers, and continues to study genetic association with sensitivity
and dynamic pain responses.
Trainees will become familiar with commonly used behavioral pain tests that we
use in the lab, online biostatistical archives and tools used to go from behavioral traits
to the underlying genetic mechanisms, and common molecular and
neuropharmacological techniques applied to the pain tests.
Ankle Block in the Rat with Ropivacaine combined with Nanoparticles – Safety and
Efficacy Studies.
Venkat Mantha, FFARCSI, William Lariviere, Ph.D.
Complications of peripheral nerve blocks from accidental intravascular injections of
local anesthetic drugs (seizures, cardiopulmonary arrest), continue to occur in spite of
taking precautions or using advanced techniques like ultrasound guidance. In our
previous research with ropivacaine combined with magnetic nanoparticles, we found
that rats tolerated a several -fold higher dose of the drug even with direct intravenous
injection. In the proposed research, in collaboration with CMU, we will combine
ropivacaine with non-magnetic nanoparticles and perform ankle block in the rat and
test its efficacy and safety compared to plain drug. The hypothesis is that the
complexes will be effective in producing the block, and safer than the plain drug. Thus,
if proved safe and effective and used in humans, the ropivacaine/nanoparticle
complexes could improve the safety of peripheral nerve blocks. The project is funded
and is approved by the Institutional animal care committee.
Students will be trained to perform ankle blocks in the rat with plain ropivacaine and
different dilutions of ropivacaine/nanoparticle complexes, and to test for efficacy of the
block. They will also perform intravenous injections of the complexes in the animals to
test for toxicity, as evidenced by immediate cardio-pulmonary arrest.
Using simulation in medical education
William McIvor, M.D., Associate Professor of Anesthesiology
By using simulation and other state of the art educational technology in the training
and assessment of healthcare system professionals, we can create a safer
environment for patients. Dr. McIvor has supervised many student SPs, in simulation
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topics including developing mannequin- and screen (computer)-based simulations.
Currently, Dr. McIvor is studying ways to automate the debriefing process after
mannequin simulations, comparing the effectiveness of screen versus mannequin
simulation, and ways utilizing simulation in medical education.
Students meet with Dr. McIvor to determine their interests and explore on-going
and potential simulation projects. They then perform literature searches to familiarize
themselves with simulation education, and create an SP that meets the graduation
requirement. Several students have presented their work at the American Society of
Anesthesiology and International Meeting for Simulation in Healthcare annual
meetings, as well as University of Pittsburgh student research forums.
Cellular Ca2+ Homeostasis in Skeletal Muscle and its Relationship to Malignant
Hyperthermia
Jerome Parness, M.D., Professor of Anesthesiology
We study the regulation of intracellular Ca2+ in skeletal muscle to excitationcontraction coupling and a rare, pharmacogenetic sensitivity to volatile anesthetics
known as malignant hyperthermia (MH).. An affected individual exposed to volatile
anesthetics responds with a massive rise in intracellular Ca 2+ in muscle which
stimulates muscle contraction and various Ca2+-dependent metabolic processes
resulting in elevated body temperatures and death. Dantrolene, a hydantoin derivative
and the only specific therapy for MH, inhibits the rise of intracellular Ca 2+, presumably
by affecting ryanodine receptor/Ca2+ channel function. The Parness lab uses
dantrolene as a probe of the ryanodine receptor and its interacting proteins, and the
molecular target(s) of dantrolene.
Trainees in Dr. Parness’ laboratory will be introduced to the field of cellular Ca2+
homeostasis as it relates to the pharmacogenetic syndrome Malignant Hyperthermia
(MH), an autosomal dominant syndrome of the hypermetabolic response of skeletal
muscle to volatile anesthetics, and the mechanism of action of dantrolene, the drug
that truncates this hypermetabolism. Trainees will learn the techniques related to
understanding the process of excitation-contraction coupling and Ca2+ release in
skeletal muscle. These include: skeletal muscle organelle isolation and gradient
centrifugation, membrane protein purification, radioligand binding techniques and
analysis, cell culture, cDNA purification, mutational analysis, PCR, transfection, and Ca
fluorescence microscopy. Trainees are expected to learn hypothesis generation,
experimental design, the importance of controls, and techniques of data analysis.
Tetsuro Sakai, M.D., Ph.D., Associate Professor of Anesthesiology
All projects are currently filled.
Visceral Inflammation and Pain
Erica S. Schwartz, Ph.D., Assistant Research Professor, Department of
Anesthesiology
To investigate the transition from acute to chronic visceral pain using a model of
chronic pancreatitis. Studies will examine the basic mechanisms that underlie the
transition from acute to chronic pain. In acute pain, tissue insult and pain generally
resolve without development of persistent pain, suggesting that the process of
nociceptor sensitization is normally reversible. In chronic pain states, nociceptor
sensitization appears to be irreversible. In pancreatitis, pain and inflammation are
predominant clinical symptoms. Experimental approaches include: whole cell patch
clamp recording, calcium imaging, and single cell PCR from labeled sensory neurons.
and procedures for the quantification of localization of ion channels, G protein-coupled
receptors, and transcription factors.
Will vary depending on the student interests but can involve anything between
behavioral assays, pharmacology, and physiology of sensory neurons to histological
analysis in isolated tissues.
Pei Tang, Ph.D., Professor of Anesthesiology
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The research is designed to determine high-resolution structures and dynamics of
proteins in the central nervous system and to investigate the interactions between
proteins and general anesthetic drugs. State-of-the-art experimental tools, particularly
multidimensional NMR spectroscopy, will be used to provide protein structural and
dynamical information as well as anesthetic binding properties. The ultimate goal is to
understand molecular mechanisms of general anesthetic action.
Students will gain hands-on experience with our state-of-the-art instruments,
including high-field NMR spectrometers, to (1) determine high resolution structures of
proteins that have been recognized as potential anesthetic targets; (2) characterize
interaction sites of anesthetic drugs on proteins and the impact of anesthetic interaction
to protein structure and dynamics; (3) evaluate potential factors that contribute to
protein aggregations and the aggregation related diseases.
Molecular Mechanisms of General Anesthesia: a Computational Approach
Pei Tang, Ph.D., Professor of Anesthesiology
This project focuses on computational investigations of the anesthetic action on ion
channels with the long-term goal of determining the molecular mechanism of general
anesthesia.
Students will receive training in computational approaches to biomedical
research. They will be exposed to the computational facility at the Pittsburgh
Supercomputer Center and learn various computational methods, including (1)
parameterizations of drug molecules for further use in molecular dynamics simulations;
(2) all-atom molecular dynamics simulations of proteins in the absence and presence
of anesthetic drugs; (3) simulations of collective protein motions using coarse-grained
models.
The Interplay of Oxidants with Nitric Oxide in the Pathogenesis and Pathophysiology of
Vascular Dysfunction
Margaret Tarpey, M.D., Professor of Anesthesiology
This project focuses on the interplay of oxidants w/ nitric oxide in the pathogenesis &
pathophysiology of vascular dysfunction, including hypertension & atherosclerosis. We
are interested in involvement of the enzyme xanthine oxidoreductase in elevated
steady state production of superoxide & hydrogen peroxide in diseased vascular
tissue. Recent studies show that moderate hypoxemia enhances expression & activity
of this enzyme. We are exploring the implication for enhanced vascular dysfunction in
patients w/ hypoxemia secondary to cardiopulmonary disease & development of sitedirected antioxidants to ameliorate local production of oxidants. The lab also develops
methods of accurate detection of these evanescent reactive species, particularly within
a biologic or clinical milieu.
Trainees will have the opportunity to study these questions from a variety of
experimental approaches, such as kinetic modeling of enzyme inhibition, molecular
and cellular biology studies of vascular cells in tissue culture, as well as organ
physiology approaches and translational studies in patients with heart failure. Such
investigations, aimed at better understanding of the chemical, biochemical and cellular
genesis of vascular dysfunction will provide opportunities to develop targeted therapies
for the increasing number of patients with cardiovascular disease.
Efficay of Phenylephrine Infusion vs. Phenylephrine Bolus for Elective Cesarean
Section
Manuel C. Vallejo, M.D., Professor, Director of Obstetric Anesthesia at MageeWomen’s Hospital
The primary aim of this study is to compare the efficacy of phenylephrine infusion vs
bolus for elective cesarean section under spinal anesthesia.
Trainees will help in the recruitment of patients, enter data and write an abstract for
presentation at a national meeting.
Inhaled Nitrous Oxide and Labor Analgesia
Manuel C. Vallejo, M.D., Professor, Director of Obstetric Anesthesia at MageeWomen’s Hospital
The primary aim is to determine if nitrous oxide can be an effective alternative
technique for the provision of labor analgesia.
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Trainees will help in the recruitment of patients, enter data, and write an abstract for
presentation at a national meeting.
Modification of Shear Induced Hemolysis by Anesthetic Agents
Jonathan Waters, M.D., Visiting Associate Professor & Chief of Anesthesiology at
Magee Women’s Hospital
The aim is to determine if red blood cell exposure to commonly used anesthetic agents
will alter the cells’ ability to withstand mechanical stress & shear forces. Subjects are
non-pregnant adults, w/ no known hemoglobinopathy, coagulopathy, or anemia, and
scheduled to receive general anesthesia. A blood sample (control) is collected from
the IV line prior to the operation. After patient induction with propofol, another blood
sample (experimental) will be obtained by venipuncture. A control sample will be used
to perform ABO typing & measure total hemoglobin. 4 samples from will be tested w/
standard protocol to determine the mechanical fragility index. Comparisons will be
made using 1-way analysis of variance.
Trainees will help with patient consenting, blood drawing, inducing hemolysis utilizing a
validated shear model, blood centrifugation, measurement of hemolysis through
spectrophotometry
Inherited Coagulation Dysfunction in Women Who Have Had a Postpartum
Hemorrhage
Jonathan Waters, M.D., Visiting Associate Professor & Chief of Anesthesiology at
Magee Women’s Hospital
Postpartum hemorrhage (PPH) is the leading cause of death during childbirth & a
source of significant postpartum morbidity. An estimated 2.5M American women have
an inherited coagulation defect which could cause/ worsen PPH. This study aims to
give an understanding of the relationship between these problems & to identify
symptoms, risk factors, co-morbidities, & adverse pregnancy outcomes associated w/ a
bleeding disorder. Our hypothesis is frequency of diagnosed bleeding disorders is
undercounted among women of reproductive age. Study designs include: case-control
study of women who had a transfusion or pharmacologic treatment for hemorrhage
with carboprost tromethamine for PPH during the past 12 years at MWH & prospective
study of women delivering during the two year study period.
Trainees will help with patient consenting, blood drawing, and data collection activities
Peripheral Nerve Blocks With Multimodal Analgesics
Brian Williams, M.D., M.B.A., Professor of Anesthesiology
Dr. Brian Williams aims to develop appropriate animal models (rat) addressing the
multimodal analgesic nerve block, in order to further advance opioid-sparing analgesia,
and aim to reduce patient dependence on opioid analgesics as the primary mechanism
of analgesia in the first week(s) after orthopedic surgery. Continuous nerve blocks have
helped to reduce opioid requirements, but are technically complicated and
subspecialized, while local anesthetics can produce unwanted motor block that may
lead to the injury of an insensate extremity. This current study is designed to develop
multimodal single-injection nerve blocks, in order to provide (i) sustained pain relief
after surgery, (ii) reduced motor block, and (iii) reduced opioid requirements.
Trainee roles include rat habituation and training, nociceptive and locomotive
behavioral testing, and data collation.
Volatile Anesthetic Interactions with Membrane Proteins
Yan Xu, Ph.D., Professor of Anesthesiology and Vice Chair of Basic Sciences
Experimental and theoretical approaches are combined to study how low affinity
neurological agents, particularly general anesthetics and alcohols, exert their effects on
the central nervous system at the molecular level. The goal is to understand the
molecular mechanisms of general anesthesia.
Trainees will have the opportunity to learn a variety of modern techniques,
including expression and purification of membrane proteins, immunohistochemistry,
high-resolution nuclear magnetic resonance imaging and spectroscopy, imaging
reconstruction, 3-D protein structure calculation, and molecular dynamics simulations
Membrane Protein Structural and Dynamical Studies by NMR
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Yan Xu, Ph.D., Professor of Anesthesiology and Vice Chair of Basic Sciences
NMR is used to determine the transmembrane domain structures of the human
glycine receptor, which is the primary inhibitory receptor in the spinal cord and
brainstem and responsible for a wide range of diseases. The long-term goal is to
provide the structural basis for novel design of drugs that are disease specific and
devoid of side effects.
Trainees will have the opportunity to learn a variety of modern techniques,
including expression and purification of membrane proteins, immunohistochemistry,
high-resolution nuclear magnetic resonance imaging and spectroscopy, imaging
reconstruction, 3-D protein structure calculation, and molecular dynamics simulations.
Gene and Stem Cell Therapy for Brain Protection and Revitalization After Cardiac
Arrest and Resuscitation
Yan Xu, Ph.D., Professor of Anesthesiology and Vice Chair of Basic Sciences
New therapy strategies are being developed to target reperfusion injury after
cardiac arrest and resuscitation. Recently, Dr. Xu’s group used umbilical cord matrix
stem cells in an effort to stop and reverse the neuronal loss after reperfusion from
prolonged cardiac arrest or stroke. A novel mechanism of extracellular signaling
between stem cells and host cells are being explored.
Trainees will have the opportunity to learn stem cell transplantation, various stroke
models, high-resolution magnetic resonance imaging (MRI), image reconstruction, and
confocal microscopy.
Glycine Receptor as a Target for Pain Medicine
Yan Xu, Ph.D., Professor of Anesthesiology and Vice Chair of Basic Sciences
From structural and functional analyses, we have identified a novel site within the
glycine receptor alpha1 and alpha3 subunits that can mediate analgesia effects of
cannabinoids without the psychoactive effects. We also developed novel channel
proteins that can be potentially used to drugs to treat chronic pain. The goal of the
project is to further develop drugs that have high affinity for the binding site identified in
the glycine receptor, and to characterize the drugs’ in vivo efficacies.
Students participating in this project will learn structure-based computational drug
design, animal models of chronic pain and behavior testing for pain evaluation, and
gene therapy and nanomedicine in treatment of chronic pain.