The central focus of our research revolves around discovering the mechanisms of anesthesia.
Molecular Pharmacology of Anesthetics
Anesthetics are considered one of the most important medical advances of all time, are used in over 100 million patients every year, and yet remain the most toxic and poorly understood of all drugs. The goal of our laboratory is a translational understanding of inhaled anesthetic pharmacology.
Biophysics of Anesthetic/Macromolecular Interactions
We have developed a wide variety of experimental approaches to study anesthetic binding to proteins, and the structural and dynamic consequences, including:
- photoaffinity labeling
- fluorescence spectroscopy
- amide hydrogen exchange
- low-affinity elution chromatography
- differential/isothermal calorimetry
- protein and peptide models (serum albumin, odorant binding protein, G-protein-coupled receptors, apoferritin, and de novo designed helical bundles)
Collaborations with mass spectrophotometry, NMR spectroscopy, x-ray crystallography and molecular dynamic simulations allow detailed atomic-level appreciation for the interactions and consequences in both time and space.
High throughput analysis of novel compounds are providing for novel anesthetic target discovery. Proteomic and genomic approaches have permitted initial forays into cell and organism implications of our binding results. Wide collaborations with many other departments and institutions have facilitated a rapid, multidisciplinary attack on some of the most fundamental questions in anesthetic pharmacology.
Anesthesia, Surgery, and Dementia
"My grandmother has never been the same since her surgery!"
Our studies on the mechanisms of anesthetic action led to the observation that anesthetics can potently promote aggregation of selected peptides and proteins, including amyloid beta. This led to our studies on the effects of anesthetics on cognition and neuropathology in Alzheimer transgenic mice. Modest effects were found but not enough to explain that common complaint by our patients. However, when we included surgery in these studies, we found that surgery significantly accelerated the onset of the neurocognitive disorder in aged 3xTgAD Alzheimer transgenic mice, which could be modulated by the anesthetic choice. Current efforts include transgenic animals, clinical biomarker studies and associative database studies.