PHILADELPHIA — A research team led by scientists at the University of Pennsylvania has received $8.6 million over the next five years in renewed grant support from the National Institutes of Health (NIH) to lead a multidisciplinary, multi-institution research program that is working to unravel the mysteries of anesthesia. The team is comprised of top medicine, chemistry, and biology researchers at the University of Pennsylvania’s Perelman School of Medicine and School of Arts and Sciences, as well as colleagues from across the Philadelphia region and Pittsburgh.
“Inhaled anesthetics are considered one of the most important medical advances of all time and are administered to over 200 million people per year worldwide. Despite their clear importance, universal acceptance, and recognized dangers, the mechanisms of their action continue to be enigmatic,” said principal investigator of the program, Roderic Eckenhoff, MD, vice chair for Research, Austin Lamont Professor of Anesthesiology and Critical Care in the Perelman School of Medicine. “This renewal of grant funding from the NIH will advance our understanding of the key protein targets of anesthetics and help us to better identify promising new agents.”
Researchers have determined that the primary, beneficial effects of anesthesia – analgesia, amnesia, immobility – are brought about by modulating the activity of specific membrane proteins in the neuronal membrane. However, the exact proteins, and how they are altered is still largely unknown, and yet critically important to improving the drugs. Progress has been slow, in part because of the many protein targets affected by these drugs, and the difficulty of studying them at the most detailed, atomic level.
Dr. Eckenhoff and his colleagues have developed a wide variety of experimental and computational approaches to study inhaled anesthetics binding to proteins, and the structural and dynamic consequences, with the hope of validating a clear pathway for how these medications put patients under. This multidisciplinary team has been collaborating on this area of research for more than 14 years, and has established that multiple different protein targets contribute to the desired effect of anesthesia, and that within each target, multiple binding sites, each with different influences on the target, exist. These complex, multilayered events are then integrated to produce the behavioral state of anesthesia. “Kind of like an orchestra,” says Dr. Eckenhoff, “each has an important contribution, but knocking out any given member has only a small effect on the music; many need to be silenced in order for the music, like consciousness, to dissipate.”
The research program includes five projects, and two cores. In addition to Dr. Eckenhoff, program collaborators include: J. Kent Blasie, PhD, Walter H. & Leonore C. Annenberg Professor in the Natural Science, University of Pennsylvania School of Arts and Sciences; William P. Dailey, PhD, and Ivan J. Dmochowski, PhD, both associate professors of Chemistry, University of Pennsylvania School of Arts and Sciences; Manuel L. Covarrubias, MD, PhD, professor of Neuroscience, Thomas Jefferson University Farber Institute for Neurosciences; Michael Klein, PhD, dean, Temple University College of Science and Technology; Patrick Loll, PhD, professor of Biochemistry and Molecular Biology, Drexel University College of Medicine; Grace Brannigan, PhD, assistant professor of Physics, Rutgers University; and Yan Xu, PhD, and Pei Tang, PhD, both professors of Anesthesiology and Structural Biology, University of Pittsburgh School of Medicine.
The renewed grant funding will continue their work aimed at achieving an understanding of the molecular pharmacology of currently used general anesthetics, and then utilizing this understanding to improve current drugs and discover new compounds for better patient care.
Penn Medicine is one of the world’s leading academic medical centers, dedicated to the related missions of medical education, biomedical research, excellence in patient care, and community service. The organization consists of the University of Pennsylvania Health System and Penn’s Raymond and Ruth Perelman School of Medicine, founded in 1765 as the nation’s first medical school.
The Perelman School of Medicine is consistently among the nation's top recipients of funding from the National Institutes of Health, with $550 million awarded in the 2022 fiscal year. Home to a proud history of “firsts” in medicine, Penn Medicine teams have pioneered discoveries and innovations that have shaped modern medicine, including recent breakthroughs such as CAR T cell therapy for cancer and the mRNA technology used in COVID-19 vaccines.
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