Stephen John Yarwood

Dr Stephen Yarwood is an Associate Professor in the Institute of Biological Chemistry, Biophysics and Bioengineering (IB3) at Heriot-Watt University (HWU). He obtained his PhD in Biochemistry from the University of Glasgow in 1998. His research interests have been aimed at elucidating the molecular mechanisms underlying inflammatory disease states, like atherosclerosis, which are normally associated with diet-induced obesity and aging. In particular, his research has focused on understanding the mechanisms regulating cAMP signal transduction, particularly the EPAC1/Rap1 signalling system in the control of vascular inflammation, and has a proven record of accomplishment in defining the mechanisms of EPAC1 signalling (H-index 30, >£2M RCUK/British Heart Foundation (BHF) funding).

Age-associated illnesses, eg cancers, cardiovascular and pulmonary diseases, neurological diseases (including Alzheimer's), diabetes, sarcopenia and autoimmune diseases, exhibit deregulation of multiple cell signalling pathways that have been linked to a sustained low-grade pro-inflammatory state. This is due to defective termination/resolution mechanisms, leading to increased levels of pro-inflammatory cytokines in the circulation, including IL-6 which leads to chronic inflammation. For example, cancers of immune and epithelial cells have a significant inflammatory component that drives proliferation, survival and pathogenic angiogenesis. These chronic diseases are the cause of 63% of all deaths worldwide and have an incidence that increases with age; consequently they account for around 70% of all healthcare spending.

We therefore need to understand fully the chronic inflammatory mechanisms associated with age if we are to maintain lifelong health and well-being in developed and developing societies. There is therefore an urgent need to identify new drug targets and develop new medicines that can prevent or reduce the chronic inflammation associated with these conditions, with the aim of improving quality of life of affected individuals. Our efforts to develop small molecules to combat age-related disease are a significant step towards this goal.

A chemical called "cyclic AMP", which is widely found in the cells of the body, normally protects the cells lining blood vessels (VECs) against the forms of inflammation associated with the development of heart disease. Current anti-inflammatory pharmaceuticals that globally elevate cyclic AMP levels (e.g. roflumilast for chronic obstructive pulmonary disorder) have undesirable side effects (eg vomiting and diarrhoea) that could be minimised by more targeted drugs that selectively and specifically activate cyclic AMP's anti-inflammatory mechanisms.

Central to the protective actions of cyclic AMP is an enzyme, EPAC1, which suppresses multiple inflammatory signalling pathways in VECs, through selective changes in gene activity. We have discovered drug-like molecules (NCN EPAC1 agonists) that activate EPAC1 in VECs and inhibit the inflammation caused by IL-6. Our aims are to determine the mechanisms of actions of NCN EPAC1 agonists, which is part of our long-term goal of transferring a detailed molecular understanding of processes that protect against chronic inflammation into new therapeutic strategies.