Disintegrin-like metalloproteases (ADAMs) comprise the major family of ectodomain sheddases. In inflammatory settings, ADAMs mediate signaling of cytokines including TNFα and IL-6 and control leukocyte recruitment by the cleavage of adhesion molecules. Several ADAMs (e.g. ADAM10, 12, 15, and 17) have been implicated in diverse common diseases associated with inflammation, including psoriasis, asthma, arthritis, atherosclerosis, ulcerative colitis, bowel disease, inflammation-associated tumours, diabetes and Alzheimer’s disease (AD). Altering protease gene expression or function might be a promising therapeutic approach to AD or other inflammatory diseases. Transcription levels in general are tightly controlled by various epigenetic mechanisms, including DNA-methylation, histone modifications and miRNA expression. The mechanisms that modulate sheddase activity have not been understood so far; for example, it is not known how the epigenetic control mechanisms interact with posttranslational modification and ADAM activity. Due to their diverse essential functions in inflammatory conditions, it is very likely that epigenetically increased or depressed protease activity may modulate local proinflammatory cytokine production and inflammatory responses.

We would like to find out whether epigenetic regulation might also modulate protease function and whether this could contribute to disease progression. The results obtained will allow insights into the transcriptional and epigenetic regulation of transmembrane proteases and the pathophysiological consequences of protease imbalance under inflammatory conditions.