Role of proteases in gastrointestinal disease

PIs: Dr D Bulmer and Professor T MacDonald, in collaboration with Professor P Enck, Professor L Ferguson, Professor D Grundy, Professor D Haller, Dr G Monteleone, Dr S Pender, Prof E Quigley, Dr J Roper, Prof M Schemann, Professor F Shanahan, Professor H Tlaskalova-Hogenova are members of a European commission framework 7 funded consortium (IPODD: intestinal proteases opportunities for drug discovery).

The aim of this consortium is to investigate and develop the therapeutic potential of protease inhibitors for the treatment of both organic (ulcerative colitis and Crohn’s disease) and functional (irritable bowel syndrome) gastrointestinal disorders. The consortium is utilizing a human tissue orientated approach to examine the genetics, develop novel hybrid human/animal and human tissue models, and evaluate novel small molecule, siRNA and antibody based therapeutic approaches to the treatment of gastrointestinal disease with a focus on protease activated receptors and matrix metalloproteases. Additionally the consortium is evaluated the human microbiome as a source of novel bacterially derived protease inhibitors.

Appetite and gastroparesis

PIs: Professor Sanger

Disorders of appetite are common and obesity in particular is a major health hazard in western society. Gut hormones are instrumental in modulating satiety and hunger, however, their precise effects on human gut function are not known in health or diseases such as obesity. We are currently using human isolated gut preparations to study the effects of different hormones released from the gut during fasting and after eating, and the distributions of their receptors within the enteric nervous system, to determine how they affect gastro-colonic motility in vivo. Some of this work is already being used by industrial partners, to help guide dose selection for novel drugs aimed at treating disorders associated with delayed gastric emptying.

Use of stem cells in treatment of gut neuromuscular disease

PIs: Mr Charles Knowles in collaboration with Dr N Thapar

The centre will help drive forward the first human use of enteric neuronal stem cells in selected patients with GI neuromuscular disease and irreversible neuronal loss. Two small pilots (first in human proof of principle and safety studies) are planned.

Role of connective tissue in gut dysfunction

PIs: Professors Aziz and Martin, Mr Knowles, and Dr Scott, in collaboration with Professor Rodney Grahame at University College London

Recent observations by Professors Aziz and Grahame suggest that 50% of patients presenting with FGID in tertiary care suffer from Benign Joint Hypermobility Syndrome (BJHS), also described as Ehlers-Danlos Syndrome Type III. Further work, just published, has shown that patients with joint hypermobility are over-represented in those referred for investigation of symptoms of disordered rectal evacuation, and that in such patients the incidence and magnitude of significant obstructive rectal wall anomalies is greater than in patients without joint hypermobility. Currently, a large case control study is underway to determine the incidence of joint hypermobility syndrome in new patients referred to secondary care.

Mechanisms responsible for the resolution of diabetes after gastric bypass surgery for obesity

PI: Professor Gareth Sanger, in collaboration with Professor Erik Näslund of the Karolinska Institute, Sweden

The aim is to elucidate mechanisms behind early resolution of diabetes after gastric bypass surgery for obesity and examine the interaction between changes in gut hormone profile after surgery and methylation status of genes related to metabolic function.