SFB854 TP2: Rolle der DNA-abhängigen Proteinkinase (DNA-PK) für entzündliche und proliferative Prozesse in der atherosklerotischen Plaque

Atherosclerosis constitutes an inflammatory and proliferative vascular disease promoted by local milieu factors, in particular growth factors and cytokines, but also genotoxic stress. During the last funding period we have identified DNA-dependent protein kinase (DNA-PK) as an enzyme crucial for smooth muscle cell proliferation in vitro and neointima formation in vivo. As well, the NF-κB Essential Modifier (IKKγ/NEMO) subunit of the NF-κB-system was found phosphorylated by DNA-PK and the serine/threonine kinase glycogen synthase kinase-3b (GSK-3b). We determined that NEMO phosphorylation is critically important for its stability and appearance within multi-vesicular bodies.  In turn, the integrity of these vesicles was found required for NF-κB activation.

The aim of the next funding period is to clarify the differential role of DNA-PK and GSK-3b in the spatial (cytosolic vs. nuclear) and temporal NEMO regulation. We will further investigate whether multi-vesicular bodies function as a signalosome for NF-κB activation or signal termination. In this context, we will study intracellular transport, nuclear translocation, protein interactions, protein-degradation and posttranslational modification of NEMO but also other subunits of NF-κB. The in vivo relevance of NEMO phosphorylation will be tested by generation of a constitutive or, if not viable, inducible knock-in mouse. These mice will be characterized and then studied under the pathophysiological condition of vascular proliferative disease induction.