Proteolysis and its regulation in health and disease

Proteolytic processing is one of the most important irreversible posttranslational protein modifications, since it affects a great variety of physiological processes critical for life, including the immune response, cell cycle, cell death, and protein and organelle recycling. Proteases are strictly controlled and imbalances in their activities have been found to be critical in a number of pathologies, such as inflammation, cancer, infectous and neurodegenerative diseases, thereby suggesting proteases as valuable drug targets. Especially in inflammation, which plays a major role in onset and progression of many diseases proteases, in particular cysteine cathepsins, caspases, and metalloproteases have very important roles. As in most of these diseases there is an urgent clinical need for improved diagnosis, therapies and patient welfare, the major focus of our program will be on cysteine cathepsins, for which unambiguous evidence for their major roles in these diseases has been provided using genetic ablation and pharmacological inhibition in animal models. In addition, caspases, legumain, various metalloproteases, and aspartic cathepsins will be investigated. However, understanding the precise role of an individual protease in a disease remains a major challenge for successful therapeutic applications. The major goals of our program are therefore: (i) to further understand molecular signaling pathways by which selected proteases regulate physiological processes in health and disease and how they are regulated, and (ii) use this knowledge for possible therapeutic interventions in disease, in particular minimally invasive diagnostic imaging and targeted drug delivery, with some work devoted to small molecule inhibitor development. To understand the signaling pathways, we would further focus on identification of physiological substrates of investigated proteases and their validation in vitro and in vivo, as well as biochemical and structural characterization of their interaction. A breakthrough can be achieved by novel multimodal imaging systems for diagnostic imaging based on Sybodies and novel targeted drug delivery systems with theranostic potential. Moreover, the identified protease substrates in the disease context have a biomarker potential, which will be explored in clinical samples. We therefore believe that this research will enhance our understanding of protease signaling pathways and their regulation in health and disease progression at the molecular level, our ability to diagnose disease and monitor its progression, and improve the existing therapeutic opportunities, which would take personalized medicine to the next level. We feel this is extremely important in the current situation, where because of the COVID-19 pandemic, a number of diseases, especially cancer were not given proper attention and many patients with advanced disease are expected to be diagnosed, requiring best possible therapies for favourable outcome.