The role of tryptases in mast cell-induced chronic inflammation

Mast cells (MCs) are long-lived tissue resident innate immune cells which induce both acute and chronic inflammatory responses. MCs are powerful effector cells in allergies, autoimmunity and protective antimicrobial immune responses. The cytoplasm of MCs is packed with granules containing inflammatory mediators such as histamine, heparin and proteases such as tryptases and chymases that are released upon activation. The release of active soluble inflammatory mediators increases vascular permeability, contributing to chronic vascular and end-organ inflammation. Recently a novel inherited human MC disorder due to α-tryptase gene duplication and triplication, characterised by inflammatory bowel and bone disease, has been identified.

The project aim is: to investigate the pathways responsible for the novel pro-inflammatory observations recently discovered in alpha-tryptasemia and thus provide a better insight into the pathogenesis of MC-induced disease. Specifically, we intend to elucidate the mechanism by which α-tryptase, previously thought to be without or with only a limited bioactivity, induces it pro-inflammatory effect on vascular and intestinal tissues.

MC-derived α- and β-tryptase functions will be studied on endothelial and epithelial cell lines. Sera as well as bone marrow-derived MC or lysates from patients with different tryptase genotypes will be added to these cell lines and transcriptional signatures, proliferative responses, activation and mediator release will be investigated. Furthermore, as tryptases are known to act via the PAR receptors, PAR receptor expression, activation and downstream signalling will be evaluated. On this basis, the proposed project devoted to the understanding of MC-mediated mechanisms and pathways involved in the induction of chronic inflammatory responses in end-organ tissues will allow for more targeted therapies for patients.

Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in the biology or immunology area / subject. Candidates with experience in immunology or cell biology with an interest in translational medicine are encouraged to apply.