Rob Semple, MB BChir, PhD

My overarching interest is in the causes and consequences of abnormal insulin/PI 3-Kinase/AKT signalling in human disease. I aim ultimately to gain insights into the nature and mechanisms of "common" insulin resistance, and into potentially modifiable mechanisms linking it to major diseases such as type 2 diabetes, fatty liver, dyslipidaemia, subfertility and cancer. To achieve this, my lab focuses first on the genetic, cellular and molecular basis of extreme human disorders of insulin action, whether genetic or antibody-mediated, and ranging from severe insulin resistance to spontaneous non insulin-dependent hypoglycaemia. Many of the conditions we study feature primary abnormalities either the insulin receptor (INSR) or downstream phosphoinositide-3-kinase (PI3K).  As well as undertaking mechanistically informative studies of relevance to common disease, I have a major translational interest in improving diagnostic pathways and therapy for patients with these rare disorders. Core approaches include physiological phenotyping of humans with rare genetic syndromes, dissection of insulin action in primary cells from affected patients ex vivo, and identification of causative genetic defects using hypothesis-led and non hypothesis-driven genetic approaches.

A second major interest of my lab arose from opportunistic discovery of postzygotic mosaic PIK3CA mutations in a family of asymmetric growth disorders in 2013. Having built a cohort of affected patients and led or contributed to pilot clinical trials, interest is now focused on collaborative studies exploiting the complementary power of human tissue transcriptomics, zebrafish and induced pluripotent stem cell modelling to seek novel mechanisms of disease, and novel therapeutic targets. These studies are focusing in particular on endothelial cell models