Proteases as novel target to treat visceral hypersensitivity

Up to 20% of individuals in the world population suffer from irritable bowel syndrome (IBS). IBS is a gastrointestinal disorder characterized by chronic abdominal pain and altered bowel habits, such as constipation or diarrhoea. It is now well established that abdominal pain in IBS patients is caused by sensitization of ion channels in sensory nerve fibres, leading to visceral hypersensitivity. We have recently identified histamine as a major mediator of visceral hypersensitivity. Moreover, blockage of the histamine 1 receptor resulted in considerable relieve in 46% of included IBS patients, confirming this pathway is indeed a valid target in IBS. Yet, other mediators must be at play to account for the non-responders. Peptidases, through activation of protease-activated receptors (PARs), can mediate pain sensation. I hypothesize that ion channel sensitization in IBS patients is mediated by overactive peptidases interacting with PAR1. To this end, I will investigate the ion channel sensitizing properties of peptidases released by the rectal mucosa of IBS patients and the role of PAR1 herein. To this end, I developed a biosensor expressing ion channels of interest and a highly sensitive genetically encoded calcium sensor. Second, I aim to identify the peptidases and their source that promote abdominal pain in IBS. The outcome of these experiments will have a direct impact on the advancement of therapeutic strategies to treat abdominal pain in IBS patients.