The overall aim of the Group is to increase our understanding of the regulation of energy metabolism. Defects in energy metabolism underlie a number of diseases including type 2 diabetes and obesity, and the prevalence of these diseases is increasing at an alarming rate. A growing body of evidence has shown that the AMP-activated protein kinase (AMPK) plays a key role in maintaining energy homeostasis. AMPK acts as a sensor of energy status and regulates a wide range of metabolic pathways, adjusting energy production with energy expenditure. We are investigating the physiological role of the AMPK cascade, with a particular emphasis on metabolic diseases. Our studies combine in vivo models in which components of the AMPK cascade have been altered genetically, together with cell based models and in vitro techniques using recombinant protein preparations. The recent identification of two upstream kinases in the AMPK cascade, calcium and calmodulin dependent protein kinase kinase (CaMKK) beta and LKB1, provides additional models and reagents with which to explore the role and regulation of AMPK. CaMKKbeta is involved in calcium signalling and so we are investigating the role of AMPK in cellular responses involving increased calcium levels. Mutations in LKB1 lead to a cancer pre-disposition syndrome in humans, termed Peutz-Jeghers syndrome, and we have begun to explore the possibility that AMPK may be involved in the regulation of cell proliferation and tumorogenesis. The specific aims of the programme are: 1. Investigating the role of AMPK in vivo using a novel gain-of-function mouse model; 2. Identification of new AMPK activators; 3. Biochemical and biophysical studies to understand the basis of AMPK regulation; examining the role of AMPK subunit isoforms in the regulation of AMPK.