Background and current state of research
The metalloproteases ADAM10 and ADAM17 are involved in the release of several transmembrane proteins with important roles in development and disease. Among the many functionally diverse substrates are cadherins, L-selectin, Fas ligand, TNF-alpha, EGFR ligands, Amyloid Precursor Protein (APP), Notch receptor and Notch ligands, as well as the IL6 receptor and TNF receptors. Looking at the multitude of diseases that a disregulation of ADAM-mediated shedding is associated with - such as autoimmune and cardiovascular diseases, neurodegeneration, cancer, infection and inflammation – it becomes obvious why the regulation of these proteases is such an important research field. Environmental factors are major contributors to chronic inflammatory disease development. Fish oil (FO) supplementation, for example, is well known for its cardiovascular-protective potential enhancing vascular integrity and preventing vascular inflammation. ADAM17 and ADAM10 are discussed to contribute to the pathogenesis of vascular diseases. As such, it is tempting to speculate whether FO supplementation might influence the expression and/or activity of ADAM10 and ADAM17 in the context of atherosclerosis.
We aim to investigate if the expression and/or activity of metalloproteases can be modulated by environmental factors. Nutritional parameters such as dietary fat composition or bioactive plant isothiocyanates are subjects of this research as well as a low oxygen microenvironment. If there are effects we would like to further investigate if there are also functional consequences, especially in inflammatory diseases.
How to get there
The influence of dietary fat composition on ADAM10 and ADAM17 will be investigated in an atherosclerosis mouse model. Wild type and low density lipoprotein receptor (LDLR)- knockout mice will be separated into two groups each and fed a western diet either containing 20 % lard or 10 % lard combined with 10 % fish oil for 12 weeks. Plasma as well as a number of organs such as aorta and liver will be collected and analyzed with different methods such as RT-PCR, immunohistochemistry, western blotting and ELISA.
Cell culture based experiments will be applied to examine the influence of isothiocyanates or hypoxia on metalloprotease function.
Two projects are in cooperation with members of the RTG: the fish oil study with Prof. Dr. Gerald Rimbach, and the hypoxia study with Prof. Jan Rupp.