Although both research areas have a completely different biological background, signalling processes are very important for the transcriptional activation of genes taking place under carnitine deprivation and CSF-1 inhibition.

The first research task is dealing with the effects L-carnitine as a nutrigenomical metabolite exerts upon gene expression. We study carnitine deficiency, itself defining a very critical clinical condition, followed by carnitine supplementation in an artificial model system in human liver and fibroblast cells. This cell culture model defines sharp metabolic condition comparable to a patient situation, a precondition to study changes on mRNA expression levels. These promoter specific processes triggered by L-carnitine will be analyzed by a variety of molecular techniques, including chip screen analysis, real time RT-PCR, reporter gene and (super) band shift assays. We already have identified genes directly involved in the transcriptional regulation of the “L-carnitine effect”, thus being able to approach clinical pathologies of hyperlipidemia, insulin resistance and type 2 diabetes mellitus, which are often very closely related. We primarily want to reveal so called “candidate or susceptibility” genes, which are associated with these diseases and have an increased sensitivity to diet (= main goal of nutrigenomics). The results of this research will provide better insight in metabolic aspects of pathologies and their regulation as well as mitochondrial function.

The second research project is tracing the effects associated with inhibition of the macrophage colony-stimulating factor (CSF-1), which plays a key role in a wide variety of biologic processes. It primarily acts on cells of the mononuclear phagocyte lineage by controlling the differentiation, proliferation and survival of precursor cells as well as the activation of mature macrophages. As the latter are present in many tissues, CSF-1 also has a role in the pathogenesis of several disorders including cancers, because it regulates the production of MMPs and the uPA gene, which are heavily involved in tissue remodeling and tumor invasion. In view of the key role of CSF-1 in tumor progression, we have investigated whether inhibition of CSF-1 expression can serve as a valuable tool to fight tumor growth and decrease the risk of metastasis. Microarray analyses have revealed very promising candidate genes that are re- or induced during CSF-1 inhibition. In theory their inhibition should enhance the inhibitory effect of CSF-1 specific antibodies or RNAi. Additional preclinical animal studies with additional inhibitory agents (monoclonal antibodies, RNAi) delineated from chip screen candidates are the next experimental aims.