The Center for Anesthesiology Research coordinates all laboratory-based research within the Division of Anesthesiology, Critical Care Medicine and Comprehensive Pain Management. The Center provides a structured, interactive environment to perform research that is both clinically relevant and fundamentally important. The clinical staff, fellows and residents have the opportunity to participate in an ongoing, productive, thematic research enterprise. The Center fosters meaningful collaborations between basic scientists and clinical anesthesiologists and intensivists and provides a forum to establish collaborative relationships with other clinical divisions and Lerner Research Institute departments.
Dr. Paul Murray investigates neural, humoral and local mechanisms that are involved in the fundamental regulation of the normal pulmonary circulation. This work serves as a foundation to investigate the effects of anesthetic agents on mechanisms of pulmonary vasoregulation, The laboratory is currently focusing on cellular and molecular mechanisms that regulate pulmonary venous tone. Interest in pulmonary veins has increased recently because a number of patients with atrial fibrillation have an ectopic electrical focus originating within the pulmonary veins. Pulmonary venous tone is a critical determinant of pulmonary capillary pressure, transvascular fluid flux and pulmonary edema. Pulmonary venous constriction may be involved in pulmonary edema formation in congestive heart failure, as well as in high altitude pulmonary edema. The laboratory is investigating the roles of the protein kinase C, tyrosine kinases and rho-kinase signaling pathways in the regulation of intracellular Ca2+ concentration and myofilament Ca2+ sensitivity in pulmonary veins. Studies are also investigating the possibility that these signaling pathways are cellular targets in anesthesia-induced changes for pulmonary venous regulation.
Dr. Derek Damron’s laboratory investigates fundamental cellular and molecular mechanisms of both normal and diabetic cardiomyocyte function. Diabetic cardiomyopathy is characterized by a decrease in myocardial performance independent of vascular disease. Diabetic patients present an additional complication in the clinical setting when presenting for cardiac surgery because induction of anesthesia typically causes myocardial depression and hypotension in otherwise healthy patients. However, the anesthesia-induced myocardial depression may also play an important mechanistic role in mediating myocardial protection, because anesthetic agents are known to reduce myocardial damage in the setting of ischemia-reperfusion injury. Despite intense investigation, the fundamental cellular and molecular mechanisms underlying diabetic cardiomyopathy are not well defined, and the molecular interactions between anesthetics and proteins involved in regulating myocardial performance and protection are even less well understood. One common link between diabetic cardiomyopathy and anesthesia-induced myocardial depression and protection is the upregulation and activation of protein kinase C (PKC) isoforms in cardiomyocytes. In particular, PKC epsilon appears to play a key role in the regulation and modulation of cellular mechanisms controlling cardiomyocyte function, and has been implicated as an important mediator of myocardial protection by anesthetic agents in the setting of ischemia-reperfusion injury. The overall goal of the laboratory is to determine the role of PKC epsilon in mediating abnormalities in cellular mechanisms regulating intracellular free Ca2+ concentration and myofilament Ca2+ sensitivity in cardiomyocytes, because these are the key regulators of myocardial contractility. Moreover, the activation of PKC by anesthetics may serve as an important molecular mechanism of general anesthesia. Gaining a detailed understanding of the structural motifs governing anesthetic-protein interactions is a critical step in elucidating the molecular mechanisms underlying general anesthesia, and will provide important fundamental information towards developing more selective and beneficial anesthetic agents.
Dr. Manju Bhat’s research has focused on investigating the role of Ca2+ channels in sensory neurophysiology and identifying the role of intracellular Ca2+ in the pathogenesis of both acute and chronic pain. His laboratory is specifically interested in studying the mechanisms and regulation of ryanodine receptor Ca2+ release channels in sensory neurons. This research is based on Dr. Bhat’s recent discovery that only nociceptive neurons contain a unique Ca2+ entry mechanism called capacitative Ca2+ entry (CCE) pathway. Current research efforts in Dr. Bhat’s laboratory are aimed at identifying the molecular components of this pathway and how it is regulated, with the goal of identifying new targets for novel pain medications. Dr. Bhat is also investigating the molecular mechanisms of action of the widely used general anesthetic, propofol. Propofol commonly causes intense pain at the site of intravenous injection. Using primary neurons and a combination of cellular and molecular techniques, the Bhat lab has discovered that propofol has selective regulatory effects on capsaicin receptors, which are known to participate in nociceptive signal transduction. Current research is aimed at elucidating the mechanisms by which propofol modulates sensory signal transduction and to examine propofol’s utility as a tool to identify new basic pain mechanisms.
Dr. Marie-Odile Parat recently joined the Center. Her laboratory investigates the role of caveolae in the physiology of endothelial cells. Caveolae are specialized plasma membrane subdomains with a distinct lipid and protein composition playing an essential role in cellular transport and signaling. Using knock-out animal models, molecular biology, cell biology, and innovative imaging approaches, Dr. Parat is pursuing her studies on the role of caveolae and their major protein component, caveolin-1, in endothelial cell migration. Endothelial cell migration is a critical component of angiogenesis, the formation of new capillaries from preexisting blood vessels. This process, which plays a prominent role in cancer, is altered in caveolin-1-null animals. Angiogenesis is required for sustained tumor growth and is prominent in diseases such as rheumatoid arthritis, diabetic retinopathy, and psoriasis. Dr. Parat also investigates whether caveolin-1 expression affects the recruitment of circulating endothelial progenitors, which contributes to post-natal neovascularization. Another project explores the role of caveolin-1 and caveolae in protein palmitoylation, a post-translational modification which may be regulated, and in turn regulate conformation, membrane association, protein-protein interactions, and intracellular localization of the target protein. Lastly, since general anesthetics often alter cardiovascular function through endothelial-dependent mechanisms, Dr. Parat’s laboratory studies the role of caveolae in the effects of general anesthetics on endothelial cells, with the long-term objective of defining strategies to prevent the cardiovascular effects of anesthesia, and new criteria for the design of future general anesthetics.