Exercise and Nutrition Research Program
Ashley is investigating the structure and function of AMP-activated protein kinase (AMPK). AMPK is an ⍺β𝛾 heterotrimeric protein kinase that senses cellular energy stress and modulates multiple metabolic pathways to restore energetic homeostasis. It is activated by stresses such as hypoxia, nutrient deprivation, and exercise. Due to its central role in metabolism, AMPK remains an attractive drug target for diseases such as type II diabetes, neurodegeneration, and cancer. Ashley’s work focuses on the AMPK regulatory isoforms 𝛾2 and 𝛾3, which remain to be structurally and functionally characterised. These are important therapeutic isoforms as 𝛾2 is highly expressed in the heart and protective in models of ischemia/reperfusion, whereas 𝛾3 is only expressed in skeletal muscle and is responsible for exercise-mediated glucose uptake. His project aims to solve the structure of 𝛾2 and 𝛾3 using single-particle cryo-EM, examine the regulatory roles of the multiple phosphorylation sites present in the 𝛾2 and 𝛾3 N-terminal extensions, and to identify small molecule activators of 𝛾3 AMPK complexes.
Ashley is working under the supervision of Professor Bruce Kemp, Dr Nolan Hoffman, and Dr Jon Oakhill.