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SFB 1192

Project B10

Proteolytic control of inflammatory glomerular disease

A diverse set of proteases are key contributors to the progression of inflammatory kidney disease.
Intracellular proteases such as cathepsins and caspases take part in signaling and fate decision
processes in kidney cells. These proteases are in close contact with extracellular proteolytic signals.
Extracellular proteases, on the other hand, convey signals of the innate immune system. As a
paradigmatic protease system, proteolytic complement activation and deposition is a hallmark of almost
all inflammatory kidney diseases. In several inflammatory kidney disease, complement inhibition is
currently evaluated as a therapeutic opportunity. Recently, our lab has developed mass spectrometry
based approaches that 1) allow to specific and direct profiling protease-generated termini (the N-
degradome) and proteolysis 2) interrogate human samples and biopsies at the single glomerulus
resolution and 3) enable the deep profiling of proteomes from all three glomerular cell types. These
approaches allow for the first time a direct monitoring of protease activity, and allow to quantify the
proteome and proteolytic activity – both intra- and extracellularly – in mouse and human glomeruli with
inflammation. We hypothesize that knowledge of proteolytic activity in inflamed tissue can be used to
intervene with kidney disease. Therefore, our overarching goal is to develop and apply these novel
methods in order to investigate and quantify proteolytic activity in humans and mice with glomerular
inflammation, while using analysis of the complement cascade as a proof of principle system. Our aims
are to 1) determine the distribution of proteases in the microenvironment of inflammatory kidney disease
tissue 2) to analyze the proteolytic processes and their contribution to protection from inflammation and
3) to study the role of complement deposition and activity in tissue pathology. In conclusion, using a
systems approach, we hope to pioneer improved stratification, and finally, management of patients with
inflammatory glomerular disease in the context of the SFB1192.