UCSF Anesthesia Research
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Dr. Bainton explores the relationship between drugs that act on the nervous system and the genetic constituents that make up that system. Specifically, he uses forward and reverse genetic screens on Drosophila melanogaster to find genes that change drug-induced behavioral outputs.
Dr. Behrends is part of the Regional Anesthesia team of the Department of Anesthesia. His clinical research focuses on how regional anesthesia improves perioperative outcome.
In collaboration with Dr. Merlin Larson, he investigates the changes of the pupillary light reflex during cardiopulmonary resuscitation. The changes of the pupillary light reflex as measured by electronic pupillometry are a potential predictor for neurological outcome following cardiopulmonary resuscitation.
Dr. Bickler studies the signaling mechanisms used by neurons to survive a lack of oxygen. These adaptations to hypoxia are studied in a wide range of models, including cells in states of suspended animation, developing neurons from the hippocampus of rats, and humans at high altitude.
Dr. Brett investigates membrane transporters, a group of proteins of great pharmacological importance because they provide the target for about 30% of the most commonly used prescription drugs. The goal of the studies is to identify sequence variants in a large number of transporter genes with known or suspected relevance to pharmacogenetics.
Dr. Caldwell investigates neuromuscular pharmacology, particularly pharmacokinetics. : Dr. Caldwell also has a major role in the development of clinical information technology systems within the Department of Anesthesia and the Medical Center. He is applying the tools of Medical Informatics and Knowledge Management, to organize and analyze the large volumes of clinical information that are available with electronic medical records.
Dr. Cason studies management and policy issues of perioperative medicine. A current specific focus is on study of surgical and ICU outcomes through use of large electronic clinical and administrative databases within the Veterans Affairs Health system. In “CALICO” – The California Intensive Care Outcomes Project, he serves as the project’s perioperative medicine expert, developing new tools and methods to measure and risk-adjust perioperative ICU outcomes.
Dr. Donegan tries to limit the spread of HIV in Indonesia by trying to decrease the spread of sexually transmitted disease and improving preventive measures.
Dr. Dubowitz studies the human physiological response to low oxygen environments. This work is done at UCSF and University of California White Mountain Research Station at 14 246ft near Bishop California. Dr Dubowitz is currently investigating intracranial pressure changes using ultrasound, cardiovascular changes observed using echocardiography and new methods of hypoxic ventilatory response testing.
Dr. Eger is defining the sites and mechanisms by which inhaled and other anesthetics produce amnesia and immobility in the presence of noxious stimuli. The approach is multifaceted, requiring studies of whole animals, neurophysiological preparations, genetic manipulations and molecular simulations.
Dr. Eilers studies the receptors and channels that comprise the peripheral nociception system. He uses molecular techniques such as heterologous expression systems, primary cultures of dorsal root ganglia neurons, microscopic Ca2+ imaging and patch clamp electrophysiology to study the TRPV family of ion channels.
Dr. Feiner studies hypoxic ventilatory drive at altitude, apnea with remifentanil and propofol, Transfusion Related Acute Lung Injury, neuromonitoring in spine anesthesia, pulse oximeter accuracy, physiology of acute anemia, predictors of kidney and liver donor organ function
Research on the Pharmacokinetics and Pharmacodynamics (PKPD) of iv anesthetic drugs (propofol, remifentanil) specially in the area of sedation-analgesia for outpatient procedures, including factors accounting for variability in drug response, sedation for Parkinson disease surgery (deep brain stimulation). Also PKPD of rocuronium in disease states.
Application of PKPD principles to the quantification of drug effects (EEG or AEP based indicators) predicted plasma and biophase concentrations or to optimal drug administration: target controlled infusion (TCI) systems
Dr. Gray has initiated several clinical trials to examine the role of nerve imaging for acute pain management interventions. He hopes to develop methods that improve nerve imaging with ultrasound to increase the efficacy and safety of peripheral nerve block procedures. Dr. Gray has recently launched a peripheral nerve imaging website available at http://nerveatlas.ucsf.edu
Dr. Gropper conducts clinical trials in the ICU focusing primarily on acute lung injury and severe sepsis. He is principal investigator of the clinical component of an NIH trial trying to identify the cause of transfusion associated lung injury (TRALI). He also has projects focused on performance improvement in the ICU, in particular resuscitation of patients with severe sepsis and prevention of catheter related bloodstream infection and nosocomial pneumonia.
Our research group is focusing on the roles of angiogenesis and vascular remodeling in vascular diseases including, intracranial aneurysms, aortic aneurysms, and brain arteriovenous malformations. These vascular lesions usually remain asymptomatic until they rupture. In case of intracranial aneurysms, rupture results in subarachnoid hemorrhage that can potentially cause severe mortality and morbidity.
Prevention of rupture of these vascular lesions is critical. We are working to identify new therapeutic targets that induce stabilization and regression of vascular lesions so that they remain unruptured and asymptomatic. We utilize novel animal models and human specimens to achieve these goals.
Investigation of ventilator induced lung injury using mass spectrometry.
Current Focus: Increased susceptibility to mechanical stretch after tobacco smoke exposure of rat alveolar type II cells.
Overview: Epidemiological data suggests that smoking may be a risk factor for the acute respiratory distress syndrome (ARDS). Based on previous investigations we postulated that smoke exposure and mechanical stretch may have additive effects leading to activation of and ultimately damage to alveolar epithelial type II cells (ATII). As in vitro model primary rat ATII were isolated and incubated for 24 h in dilutions of cell culture medium that had been exposed to smoke from standardized research cigarettes. Smoke content was normalized by spectrophotometry. Subsequently, some cells were mechanically stretched for 6h using a Flexcell cell stretch apparatus. Cell viability (Luminescence assay), protein content (Bradford), HSP 70 content (ELISA) and proteomics analysis (iTRAQ and LC-MS-MS) were performed. To determine in vivo effects, SD-rats were exposed to the smoke of 3 research cigarettes a day for two weeks (Group S and NS), then some rats were anesthetized and mechanically ventilated for 4 h (Groups V and NV). Animals were sacrificed, BAL was performed and ATII were isolated. BAL protein content, cell differential and proteomic analysis were done. Results: In vitro, increased smoke and stretch had additive effects on HSP 70 content and decreased cell viability. In vivo, an additional increase in airspace neutrophilia and BAL protein content was observed after co-exposure. Quantitative proteomics with multidimensional separation discovered alterations in cellular protein content. In conclusion, exposure to cigarette smoke may increase the risk for ventilator associated lung injury.
Dr. Kim is a genetic epidemiologist working at the Center for Cerebrovascular Research. She is investigating genetic and environmental factors that predict hemorrhagic stroke and/or poor outcome in patients with cerebral vascular malformations.
Dr. Kolodzie is conducting clinical research on a wide range of perioperative outcomes, including but not limited to postoperative nausea and vomiting, postoperative pain management after orthopedic surgery and perioperative cardiac arrhythmias. She performs evidence based quantitative systematic reviews, epidemiological research and controlled clinical trials.
Dr. Larson in collaboration with Dr. Niemann, investigates the interaction of the anti-fungal agent fluconazole on the pharmacodynamics of intravenous fentanyl in old and young patients. He also uses pupillary light reflex to investigate changes in depth of general and regional anesthesia.
Dr. Lee investigates the mechanisms of key pathways on cerebral angiogenesis and vascular malformations using pharmacological and genetic manipulations.
Dr. Lee The main focus of his research is understanding the potential therapeutic role of allogeneic human mesenchymal stem cells in acute lung injury. To study this, I have developed three human models: (1) A fairly novel ex vivo perfused human lung injured by E. Coli endotoxin. (2 & 3) Primary cultures of both human alveolar epithelial type II cells and human lung microvascular endothelial cells grown on Transwell plates injured by an inflammatory insult.
Dr. Leung investigates methods to improve perioperative care delivery and outcomes of older surgical patients. Examples of ongoing projects include cohort study and clinical trials on postoperative delirium and postoperative cognitive dysfunction.
Dr. Litt uses ex vivo rat brain slices to investigate how intracellular energy metabolism of neurons and glia relates to brain injury and protection during hypoxia and ischemia. Mitochondria send out signals to start and stop apoptosis and necrosis. 31P, 13C, and 1H NMR spectroscopy at 14 Tesla are used to track metabolite changes. Mitochondrial signals associated with injury and repair are detected from changes in proteins, their phosphorylation, and also from redox states. Studies are done in whole slices, slice extracts, and cell fractions obtained with differential centrifugation. Cell biology techniques include Western blotting, immunohistology, in situ hybridization, and fluorescence microscopy.
Dr. Liu's research focuses on using a combinatorial antibody library approach to identify novel human monoclonal antibodies that target tumor and tumor stem cells. Currently the lab is working on three main research projects: (1) We are identifying human single chain antibodies that target clinically represented tumor cell surface antigens by combining phage antibody display with laser capture microdissection. We are also determining the molecular identify of tumor cell antigens targeted by these antibodies. (2) We are identifying human single chain antibodies targeting tumor stem cells, which have been hypothesized to be the root of the tumor hierarchy. (3) We are developing novel targeted systemic siRNA/miRNA delivery vehicles based on tumor- and tumor stem cell-targeting internalizing human antibodies.
Dr. London analyzes the efficacy and effectiveness of various perioperative therapies and procedures in high risk patients undergoing vascular and cardiac surgery, including beta blockade, pulmonary artery catheterization, transesophageal echocardiography, and early extubation in large patients cohorts in the Department of Veterans Affairs using clinical databases.
Role of Pre-eclampsia on lung endothelium.
Effect of Pre-eclampsia on oxygenation.
Dr. Marks investigates the mechanisms of botulism toxicity and produces human antibodies that block the toxicity. His lab produces human antibodies using phage display techniques.
Dr. McKay designs and conducts clinical studies related to 1) respiratory complications in patients undergoing anesthesia where an LMA is used for airway management; 2) respiratory complications and recovery of cognition and return to functional activities after anesthesia in smokers; 3) temporal recovery of protective airway reflexes after anesthesia in relation to awakening; 4) the effect of body mass index (BMI) on recovery from inhaled anesthetics of differing solubility in tissues (sevoflurane versus desflurane). Another project is an industry sponsored multicenter trial on the safety and efficacy of the oral neurokinin inhibitor GW679769 in prevention of nausea and vomiting after surgery.
Dr. Niemann investigates ischemia/reperfusion injury in organ transplantation. He also evaluates liver function and splanchnic hemodynamics in liver transplant patients and in living liver donors.
Dr. Pawlikowska is an Assistant Professor in the Department of Anesthesia and Perioperative Care. Her research focus is genetic association studies of common human disease of complex inheritance, including cardiovascular phenotypes and longevity. In collaboration with Drs. William Young and Helen Kim, she studies the genetics of vascular phenotypes, focusing on brain arteriovenous malformation (BAVM), an important cause of stroke in young adults. Candidate-gene approaches have yielded several variants associated with BAVM incidence or clinical course; genome-wide association studies (GWAS) are underway. Other approaches planned include mapping modifier loci for angiogenesis in mice, screening for rare variants using high throughput sequencing technologies, and investigation of somatic genetic variation in BAVM tissue samples.
A second focus of Dr. Pawlikowska's research is on genetics of human aging and longevity. She is part of the NIA-funded Longevity Consortium. She has been involved in quantitative trait locus mapping in a long-lived mouse strain and in candidate-gene studies of human longevity including the insulin-IGF signaling pathway. Future projects include high-throughput sequencing to discover rare variants in genes in longevity-associated pathways.
Third, Dr. Pawlikowska is developing a research program in admixture mapping of cardiovascular disease traits in admixed populations such as African Americans. She is the principal investigator on an R01 proposal to map metabolic syndrome traits, funded by the NIDDK.
I work in the laboratory of Dr. Judith Hellman, under the mentorship of Dr. Jean-Francois Pittet and Dr. Judith Hellman. My research focuses on the molecular mechanisms behind reperfusion injury using the lung as a model system. Specifically I am going to study the transcription factor HMGB1 that has been identified as a damage associated molecular pattern (DAMP), that engages the innate immune system and inflammatory pathways during times of tissue/organ damage and following reperfusion. DAMPs signal via surface receptors in a remarkably similar manner to pathogen associated molecular patterns (PAMPs) such as virus associated double stranded RNA and bacteria associated LPS. Using my background in molecular and cellular immunology, I hope to identify cellular and molecular targets, whose modulation may alter the excessive immune/inflammatory responses seen in ischemia/reperfusion injury. This work could thus prove valuable in understanding the organ and cellular injuries seen following hemorrhagic shock, cardiac arrest and organ transplantation and may suggest potential therapeutic targets.
Dr. Rollins investigates means of improving oxygen delivery both to acute wounds (e.g., maintaining normothermia and administering 100 percent oxygen intraoperatively) and to chronic wounds (e.g., sympathetic blockade, local warming and hyperbaric oxygen therapy). This involves studies in animal models, human volunteers, and patients, along with developing better oxygen measuring techniques.
Dr. Russell focuses on intraoperative transesophageal echocardiography with particular interest in infants and children with congenital heart disease. In cardiac adult patients, current projects include the utility of myocardial contrast echocardiography via TEE as a novel approach to objectively analyze myocardial perfusion.
Dr. Sall studies the effects on anesthetics on neurogenesis, especially neuronal stem cells that are the precursors of new neurons within the brain.
Dr. Schumacher investigates the structure, function and genomic regulation of ion channels that are activated by noxious stimuli. Through the study of the capsaicin receptor (TRPV1/VR1) and its family of related ion channels, Dr. Schumacher and his lab hopes to one day develop a means to selectively block acute and chronic pain at the level of the peripheral sensory nerve terminal.
Dr. Schumacher's famous paper on capsaicin published in Nature.
Dr. Sonner investigates the mechanism of inhaled anesthetics. He studies anesthetic effects on expressed ion channels and in animals. His projects include: a gene mapping study in mice which differ in their anesthetic requirement; investigations on experimental anesthetics, including compounds elevated in metabolic comas, which are hypothesized to act as endogenous anesthetics; and he is developing yeast models to investigate basic biologic effects of inhaled anesthetics.
Dr. Stratmann studies the effects of anesthesia on brain stem cells and new neuron formation. He uses a comprehensive approach including immunocytochemical, electrophysiological and behavioral techniques. Phil Bickler and Jeff Sall collaborate closely on this topic with the aims of optimizing cognitive outcome following anesthesia at different ages and developing clinical applications to enhance brain self-repair following perioperative insults.
Hua Su, MD
Dr. Su is interested in angiogenic gene and cell therapies for ischemic organs and tissues, and the mechanisms of angiogenesis. Her current research includes:
1. Developing strategies to treat brain ischemia by promoting functional angiogenesis and neurorestoration. Dr. Su is testing the feasibility of using adeno-associated viral vector (AAV) mediated hypoxia-inducible angiogenic gene expression to induce angiogenesis at ischemic core/penumbra of ischemic brain. Funded by a grant from the CIRM stem cell program and collaborating with Dr. Samuel Pleasure in the Dept. of Neurology, she is using human stem cell derived oligodendrocytes to regenerate injured brain. She is also collaborating with Dr. Fen-Biao Gao at Gladstone Research Institute, studying the roles of micro RNA in neuron stem cell differentiation, migration and in brain injuries
2. Studying the mechanisms of brain AVM pathogenesis and developing a clinically relevant model of brain arteriovenous malformation (AVM). The etiopathogenesis of brain AVM remains unknown and research progress is critically hampered by the lack of animal models. In collaboration with Dr. William Young and other scientists in the Center for Cerebrovascular Research, Dr. Su is using the following strategies to develop brain AVM model in the adult mouse: (1) genetic manipulation using transgenic or knockout mice; (2) block ligand-receptor binding by overexpression of soluble proteins; (3) focal angiogenic stimulation by AAV mediated VEGF gene transfer; and (4) altering hemodynamic forces in the brain by pharmacological manipulation or surgical creation of arteriovenous shunting.
Dr. Talke investigates the physiology and pharmacology of highly selective alpha-2 agonists in humans and in animals. He currently concentrates on the effect of different alpha-2b genotypes on vascular responsiveness in humans.
Dr. Wallace is a biomedical engineer who investigates methods for the reduction in perioperative cardiac risk. He is working on a project to implement perioperative beta blockade throughout the VA and Kaiser Medical systems. Dr. Wallace works on anti-ischemic drug development as well as device development to make cardiac surgery safer.
Dr. Yost studies a special class of potassium channels that may contribute to the mechanism of action of volatile anesthetics. In addition his lab investigates the molecular pharmacology of other ligand-gated ion channels, such as the GABAA, glycine, 5-HT3 and NMDA receptors with respect to other drugs used in anesthesia.
Dr. Young focuses on clinical studies of brain hemorrhage, including arteriovenous malformations and intracranial aneurysms. A major emphasis is on using genomic techniques to identify risk of poor outcome as well as disease susceptibility. Laboratory studies include modeling of intracranial vascular malformations that include models using growth factor stimulation to simulate human disease. There is emphasis on the contribution of vascular inflammation and various kinds of progenitor cells in mounting abnormal vascular remodeling. Other studies include use of cell and viral therapy to protect or resuscitate the brain from ischemic injury.