FWF Lipotoxicity: Lipid-Induced Cell Dysfunction and Cell Death

Transcriptional regulation of lipotoxic pathways The goal of the SFB-LIPOTOX is to unify relevant research forces in Graz on one theme: Lipotoxicity. The research consortium defines lipotoxicity as the anomalous uptake, generation, and activity of lipid derivatives mediating adverse, "lipotoxic" effects including dysregulation of metabolic pathways, cell- and organelle dysfunction, and cell death. To investigate lipotoxicity as a pathological basis of human disease and to discover molecular processes that can prevent lipotoxicity, we propose to identify and characterize the molecular and cellular mechanisms activated by lipotoxic substances. Genomic, proteomic, and lipidomic technology will be utilized to discover novel lipotoxic pathways. Mutant mouse and yeast models will be analyzed to elucidate the mechanisms that cause the production of toxic lipid compounds, lead to cellular dysfunction, and induce apoptosis or other forms of cell death. It is evident that such a broad scientific aim requires a conceptual strategy that supersedes the singular focus of individual research groups, and that ensures effective exchange of ideas, expertise and resources. The SFB program of the FWF provides the appropriate framework for a dynamic and interactive research consortium embedded in a number of related project programs. We expect our findings to contribute to the identification of valid targets for disease intervention. Specifically, we aim in our subproject to: Identify gene sets and pathways associated with lipotoxicity across tissues and species by comparative computational genomics. In this project we will be able for the first time to perform comparative analyses of genes and pathways involved in lipotoxicity across tissues and species. Using data from adipose tissue, muscle, heart, liver, macrophages, and neurons we will be able to identify gene sets and pathways selectively and commonly expressed in the mouse models of lipotoxicity. We will then explore the relevance of the identified targets for human disease by comparative analyses of expression profiles.