Background: While modern medicine is very successful in treating a great variety of acute diseases, a common feature of hard-to-control diseases such as arteriosclerosis, cancer and neurodegenerative diseases is chronic inflammation. Currently, no diagnostic options exist to detect chronic inflammation such as arteriosclerosis or tissue fibrosis at early stages. Quite importantly, chronic inflammation is a common feature of the tumor microenvironment, providing the link to research project I (see above). Early detection as well as a more profound understanding of mechanisms responsible for chronic inflammation would allow us to pioneer novel treatment options. Currently applied antiphlogistic drugs mainly target white blood cells, which are rather short-lived cells and therefore hardly responsible for the maintenance of inflammation. In contrast, long-lived cells such as endothelial cells and fibroblasts are important contributors to chronic inflammation. Responsiveness of these cells to established antiphlogistic drugs has hardly been investigated.

Methods and Models: Molecular profiling (I, II) targeted analyses (III) and cell culture (IV). To investigate realistic scenarios, we prefer primary human cells for these investigations, as transformed cell-lines do not act in a representative manner. White blood cells are isolated from venous full blood and endothelial cells from umbilical veins or from clinical tissue samples. Fibroblasts are isolated from bone marrow and other tissue samples. Cell isolation is accomplished using magnetic activated cell sorting (MACS) technology. Cells are inflammatory activated by treatment with lipopolysaccharide (LPS), phytohaemagglutinin (PHA) or interleukin-1beta. In addition, cells are optionally treated with steroidal and non-steroidal antiphlogistica. Cell responses are investigated using proteome profiling, targeted proteomics, lipidomics and metabolomics.

Aims: The establishment of cell type-specific inflammation signatures shall allow us to assign inflammatory activities in humans to the main players with respect to cell types of the corresponding diseased tissues. Combined detection of cytokines and lipids may allow us to diagnose arteriosclerosis and risks for neurodegenerative diseases at early stages. Furthermore, our aim is to identify resistance signatures indicating that some kinds of drugs may not work as expected. The interplay of proteins, lipids and metabolites recorded by us during inflammation and features of treatment-resistant samples shall indicate novel ways to interfere with chronic inflammation.

Collaboration partners:

• Prof. Brigitte Marian, Department of Medicine I, Medical University of Vienna

• Prof. Dr. Siegfried Knasmüller, Department of Medicine I, Medical University of Vienna

• Prof. Dr. Andreas Rizzi, Faculty of Chemistry, University of Vienna

• Dr. Iris Ribitsch, University of Veterinary Medicine Vienna

• Dr. Ronald Ullmann, Syntrion, Germany