Protease Systems Biology

Protease network degradomics

Proteases play pivotal roles in many diseases and form 5-10% of all potential drug targets. It is now clear that detrimental proteolysis results from perturbation of a complex proteolytic network rather than altered activity of a single enzyme. Disturbances of such networks lead to severe diseases including cancer and inflammatory disorders. However, so far technical limitations prohibited a global understanding of interconnected protease activity in complex systems, contributing to devastating failures of protease inhibitors in clinical trials.

Our research group develops and applies novel proteomics technologies to understand protease networks in inflamed tissues and hyperproliferative epithelia focusing on the skin as model system. Targeted assays discriminate pro- from active proteases, and our next-generation positional proteomics workflows allow analyzing small sample amounts from cells and tissues obtained from animal models and patient biopsies.

In translational research, we monitor and functionally characterize protease substrate cleavages as net outcomes of complex proteolytic activities in healing impairments, a common complication in elderly people and patients suffering from diabetes. In collaboration with clinicians, we apply approaches that we have implemented using clinically relevant wound models to the analysis of wound samples from patients with normal and delayed healing.

These studies will relate proteolytic modifications to protease subnets and their disturbance in disease. In the future, we will extend these subnets to ultimately map the entire protease web in protease-related disorders and to build predictive models that allow evaluating proteases as diagnostic indicators and therapeutic targets within the scope of personalized medicine.