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.
We want to
- learn more about the regulation of ADAM functions in particular on the transcriptional level
- gain insights into the epigenetic regulation of ADAMs and related transmembrane proteases (beta-secretase) in normal tissues and inflammatory diseases including psoriasis, IBD, AD and inflammation-associated cancers including lymphomas
- find out how epigenetic regulation and differences in ADAM expressions might influence the pathogenesis of different inflammatory diseases
We want to reach our goals by
- examinging the analyses of the expression of ADAM family members and BACE in inflamed and normal tissues on mRNA and protein level (bullous pemphigoid, systemic lupus erythematodes, psoriasis, IBD)
- carrying out a functional analysis in the context of the disease
- completing a DNA methylation pattern analysis with HumanMethylation 27k or 450k Bead Array (Illumina, Inc.)
- researching of the relationship between epigenetic regulation and the pathology of the disease
 Reiss, K and Saftig, P (2009) The “A Disintegrin And Metalloprotease” (ADAM) family of Sheddases: Physiological and Cellular Functions. Semin Cell Dev Biol. 20:126-37.
 Le Gall, S, Bobé, P, Reiss, K, Horiuchi, K, Niu, XD, Lundell, D, Gibb, DR, Conrad, D, Saftig, P, Blobel, CP (2009) ADAMs 10 and 17 are differentially regulated components of the shedding machinery for TGFα, TNFα and other membrane proteins. Mol Biol Cell. 6: 1785-94.