How we think, eat, breathe and move is ultimately controlled by the movement of ions across cell membranes that controls the electrical activity of cells in our body.  My lab is particularly interested in how potassium ion channels, are regulated by both post-transcriptional and post-translational mechanisms and importantly how dysregulation may lead to major diseases including stress related disorders, obesity, high blood pressure and diabetes.  We take an Integrative Physiology approach examining from the level of single ion channel proteins to whole body function.

Work is currently focused in three main areas:

S-acylation and the physiology of calcium-activated (BK) channels:

Dysregulation of calcium-activated (BK) potassium channels may lead to major human disorders such as obesity, diabetes and high blood pressure. Understanding how these channels are regulated by both environmental (e.g. diet, stress, drugs) as well as genetic (e.g gene mutations) factors is thus crucial to understanding both the causes of such diseases and allow us to define new therapeutic strategies to treat them.

Addressing these issues also underpins one of the major challenges in post-genomic biology: understanding how we generate physiological diversity from a limited genome. My laboratory focuses on the role of the major post-transcriptional ( e.g. alternative pre mRNA splicing) and post-translational (e.g. phosphorylation, S-acylation (palmitoylation)) drivers for generating proteomic diversity, in controlling BK channel properties and physiology.

We are trying to understand how interaction between these processes and the physiological consequence of changes in these pathways controls defined physiological systems. In particular, recent work has focussed on S-acylation (palmitoylation), a reversible post-translational lipid modification, that controls the trafficking of BK channels to the cell surface as well as their activity and regulation by phosphorylation-dependent signalling pathways. Funded by the Wellcome Trust, British Heart Foundation, and Diabetes UK we take a multidisciplinary approach to understand how S-acylation controls channel properties and physiology from analysis of single ion channel signalling complexes to analysis of channel function at the systems level using conditional knockout strategies.

Ultradian rhythmicity in the stress axis

Our ability to respond and cope with stress is ultimately controlled by the electrical activity of cells within the neuroendocrine stress axis: the hypothalamic-pituitary-adrenal (HPA) axis. A bit of stress is good for us but prolonged or excessive stress can lead to major cardiovascular, metabolic and affective disorders. The stress axis is controlled by both a 24hr (circadian) and an ~ hourly (ultradian) rhythm and disruption of the rhythmical release of stress hormones is associated with disease. In a Medical Research Council- funded programme we are trying to understand how the excitability of corticotroph cells in the anterior pituitary in the control of the ultradian rhythm and gain better insights into how we may more effectively treat stress-related disorders.

Gut-brain interaction: Full4health

As a partner in a 9M euro study, Full4health, we are using optical techniques to manipulate neuronal activity to examine the role of the brain in the sensing of energy balance and the initiation of food intake. As well as leading to a greater understanding of signalling between the gut and the brain, it is hoped that the findings will help inform the food industry as to how food could be formulated to help tackle obesity and under-nutrition.

We are funded by the Wellcome Trust, Medical Research Council, British Heart Foundation, Diabetes UK and EU FP7