PI: currently none Rat Models for Metabolic Disorders

The goal of the current biomedical research is to reveal genetic determinants of common diseases, including cardiovascular and metabolic disorders which often occur together and are diagnosed as the metabolic syndrome, a complex trait arising from of intertwined network of genomic and environmental components.
The overall aim of our project is the systematic deconstruction of eco-genomic architecture of the metabolic syndrome. We are pursuing this goal using genetically designed rat models with modulated gene expression (single genes or metabolic/signaling pathways). We are particularly focusing on four major aspects of metabolic syndrome eco-genomic “landscape”.

Early environment and metabolic programming of metabolic syndrome. Our initial studies showed that the metabolic and hemodynamic outcomes of early environment challenges are to a certain extent dependent on the genomic background. We are set to determine major metabolic (biomarkers), transcriptomic (transcripts, pathways) and epigenomic (methylation) features related to developmental drivers of particular subsets of metabolic syndrome as seen in clinical setting.

Genetical genomics of metabolic syndrome. This approach involves identification of signaling and expression modules playing a role in pathogenesis of metabolic syndrome and its aspects. By combining the existing and newly generated –omics level data from designed rat models of metabolic syndrome we are seeking the sex, age and organ-specific expression and signaling networks and playing crucial roles in pathogenesis of the metabolic syndrome.

Nutrigenomics and pharmacogenomics of metabolic syndrome. Reflecting the complex network of dietary and pharmacological influences that only together with the genomic background make up the clinical presentation of metabolic syndrome in real life, we are systematically dissecting the diet-modulated, pharmacogenetic interactions we have previously described e.g. for the antidiabetic drug rosiglitazone. We are testing the effects of westernized diets and commonly used drugs known to affect features of metabolic syndrome when acting on specific genomic backgrounds in the designed rat models.

Towards integrative eco-genomics of metabolic syndrome. By integration of the results from the above project and the available date we aim to proceed beyond the identification of individual risk and protective variants using the tools of system biology (analysis and modeling of genetic and signaling networks). This effort should lead us towards identification of functional genomic signatures connected with manifestation of specific forms of metabolic syndrome.