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We investigate the effects L-carnitine exerts as a nutrigenomical metabolite upon gene expression. Based on chip screen analyses collections of genes were identified to be involved in the transcriptional regulation of the “L-carnitine effect”. We primarily want to reveal so called “candidate or susceptibility” genes, sensing L-carnitine levels and how they are involved in clinical pathologies like as hyperlipidemia, insulin resistance and type 2 DM. The results of this research will provide better insight in metabolic aspects of pathologies and their regulation as well as mitochondrial function. A second research area is focused on the use of a super-active human thymidine kinase 1 to treat solid tumors. This recombinant superTK1 was generated by structure-based site directed mutagenesis and integrated in eukaryotic vector systems and transferred into tumor cells. Based on the super-active TK1 we only need very minute amounts of deoxythymidine to induce cytostatic and toxic effects.
In a cell culture model system of human liver, fibroblast and muscle cells we mimic carnitine deficiency, followed by carnitine supplementation. The mRNA expression levels as well as signaling events of specific genes are analyzed. In addition the metabolomics of relevant metabolites like as betain, L-carnitine/esters, AcCoA etc. will be analyzed in cooperation with the Metabolomics Unit of the VBFC. This will allow us to define the “metabotranscriptomics” of L-carnitine in conjunction with genomics and signaling. The treatment of solid tumors is going to be performed with xenotransplants in mice of human mamma, prostate and glioblastoma cancer cells. The experimental tumors will be treated with superTK1 integrated in eukaryotic vector systems (pUHDhygr, recAAV). In addition novel infiltration platforms based on biopolymers, bioinks and 3-D printed nanoneedles are being developed within this project together with the Centers of Medical Biophysics and Biomedical Research of the MUW.
Reinhold Hofbauer studied Biochemistry at the Univ. Vienna and received his PhD (1985). From 1987-1988 Reinhold went as a postdoc to Prof. Dr. D.T. Denhardt (Cancer Research Lab, Univ. of Western Ontario, London, Canada) as an Erwin Schrödinger fellow. In 1997 he got tenured at the MUW and is since then group leader and Ass.Prof at the Center of Med. Biochemistry, MFPL, MUW
The engineered superTK1 is locally administered to tumor cells as gene therapeutic (AAVsuperTK1). Cytostatic as well as cytotoxic effects on tumor cells are exerted in a time dependent manner at very low deoxythymidine levels (dTh ≥ 10µM). In the case of systemic exposure these very low dTh concentra¬tions hardly entail any side effects to healthy cells and the organism. Combination treatment with cytostatics (e.g. 5-FU, AraC) is possible in a similar low concentration range (5µM). Therefore marginal side effects without diminishing treatment efficacy can be expected.
L-carnitine has an apparent time-dependent effect on the activity of the vitamin D nuclear receptor pathway. Supplementation of L-carnitine to WRL68 liver cells for 4 hours leads to an immediate increase in activity of the vitamin D signaling activity (up to 2.88-fold induction). However after 24 hours this effect cannot be observed anymore since L-carnitine got completely metabolized in this fraction of time. This example clearly shows the immediate effects L-carnitine has on some important nuclear receptor pathways.
Thrombospondin-1 binds to ApoER2 and VLDL receptor and functions in postnatal neuronal migration.
Blake, Sophia M; Strasser, Vera; Andrade, Nuno; Duit, Sarah; Hofbauer, Reinhold; Schneider, Wolfgang J; Nimpf, Johannes
L-carnitine and PPARalpha-agonist fenofibrate are involved in the regulation of Carnitine Acetyltransferase (CrAT) mRNA levels in murine liver cells
Kienesberger Klemens, Pordes Ginta Aniko, Völk Georg Thomas, Hofbauer Reinhold