Description of Research Expertise MOLECULAR PHARMACOLOGY OF INHALED ANESTHETICS Discovery of the general anesthetics is considered one of the most important medical advances of all time. They are used in over 100 million patients every year, and yet remain the most toxic and poorly understood of all drugs. The goal of my laboratory is a translational understanding of general anesthetic pharmacology, but focused at the most fundamental molecular level. This is a critical foundation on which the subsequent superstructure of molecular, cellular and organism understanding will be built. We have developed a wide variety of experimental approaches to study anesthetic binding to proteins, and the structural and dynamic consequences. Thus, photoaffinity labeling, fluorescence spectroscopy, amide hydrogen exchange, low-affinity elution chromatography and differential/isothermal calorimetry have all been introduced and validated for this purpose. We have moved from simple protein and peptide models to the most relevant and complex ion channels, enzymes, and receptors. We collaborate with Penn Chemistry (William Dailey, Ivan Dmochowski) to introduce novel reagents into our campaign to understand molecular anesthesia. Wide collaborations with many other departments and institutions have facilitated a rapid, multidisciplinary attack on some of the most fundamental questions in anesthetic pharmacology. NEURODEGENERATIVE DISORDERS Our studies of general anesthetics have led to the observation that they can potently promote aggregation of selected peptides and proteins, as well as modulate the immune response. Since a common feature of most neurodegenerative disorders is aggregation of endogenous peptide, and neuroinflammation, the general anesthetics may accelerate the onset of neurodegeneration. Examination of the effects of anesthesia and surgery in a fully translational manner is a growing focus of our laboratory.