THE TRAP5/OSTEOPONTIN-AXIS – A NOVEL TARGET TO TREAT AIRWAY INFLAMMATION

Chronic airway inflammation results in tissue injury, remodeling, and, in severe cases, respiratory failure. This is exemplified by COPD and non-allergic asthma where current treatments have limited efficacy.

In this project, we will investigate how tartrate-resistant acid phosphatase 5 (TRAP5) of alveolar macrophages interacts with osteopontin (OPN) produced by airway epithelial cells, thereby modulating airway innate immunity.

The following will be investigated:The expression and activation of the phosphatase TRAP5 as well as small molecular compounds inhibiting its activity will be investigated in vitro.

The in vivo importance will be studied using models of airway inflammation and infection in TRAP5 knockout mice.The importance of modifications (i.e. the degree of phosphorylation and transglutaminase-mediated cross-linking) of OPN will be investigated in vitro and in vivo.

In particular, there will be a focus on how TRAP5 and OPN interact to recruit neutrophils during airway inflammation and infection.It is important to increase the understanding of how TRAP5/OPN can play such crucial roles in recruiting neutrophils to the airways during inflammation, infection, and remodeling.

In vitro and in vivo models of acute and chronic airway inflammation will be used to elucidate the hitherto largely unknown mechanisms involved.

Results from the project will provide unique opportunities to better target inflammation and subsequent remodeling in severe airway inflammation.