Grant: Project Grant

Surgeries are meant to be procedures that improve or even save lifes. However, complications during surgery can always arise unexpectedly. One such complication arises from the anaesthetics that are being used. Some people are at risk for an event called 'malignant hyperthermia' (MH). They normally don't have any symptoms until they undergo surgery. The anaesthetics used cause a massive rise in body temperature, the muscles become rigid, and the body goes into a hypermetabolic state that usually results in death. The reason for this disease is genetic. Most people susceptible to MH carry a mutation in a gene called 'RYR1'. The gene makes a protein known as the 'Ryanodine Receptor' and it plays a critical role in the contraction of our muscles. Somehow, the anaesthetics and the mutation cooperate: neither alone is enough to cause the protein to malfunction, but the combination of the two is deadly. In this project, we aim to understand how exactly malignant hyperthermia arises , as well as how the protein involved in the disease is being regulated. In particular, we will create very high-resolution 3D structures of the Ryanodine Receptor protein. By comparing the protein from 'normal' people versus people carrying a disease mutation, we will figure out how exactly the mutation alters the 3D structure. We will also look at the effect of various anaesthetics on the 3D structure. Understanding this may pave the way for next-generation anesthetics that no longer have dangerous side effects. Next, we will investigate how exactly the Ryanodine Receptor protein is being regulated. To do this, we will create 3D structures of this protein in complex with another critical muscle protein that we know interacts with it. We will also make use of muscle cell lines to investigate how this regulation works inside cells.