29 February 2016

PhD student Dimitris Nasias about his research within the RESOLVE project

As a Phd candidate, my main interest is directed towards the understanding of the molecular networks underlying complex diseases. I am really keen on performing high throughput transcriptomic analyses in order to achieve global expression profiles and thus to identify their relevance in health and disease. Our research aims to monitor global changes in the gene expression profile of the liver and other tissues during the pathogenesis of the metabolic syndrome using the ApoE3L.CETP mouse as an experimental model. ApoE3Leiden.CETP mice display all the clinical features of the metabolic syndrome upon feeding a western type diet. The metabolic syndrome (MetS) is a group of clinical disorders including abdominal obesity, elevated blood pressure, loss of glycemic control, high triglycerides and low HDL cholesterol, whereas MetS patients are at increased risk for developing cardiovascular disease and type-2 diabetes. The molecular background of the MetS is poorly understood, whereas effective diagnostics and therapeutics are urgently needed. In our experiments, ApoE3L.CETP male mice are fed either a High Fat Diet (HFD) or Low Fat Diet (LFD) for 4, 8 and 12 weeks. RNA specimens from liver and other tissues are analyzed using Affymetrix microarrays followed by extensive bioinformatical analysis. The differentially expressed genes (HFD vs LFD for each time point) are annotated according to the Gene Ontology Classification. Further categorization of genes into pathways and networks of interactions give an insight into the biological significance of the differentially expressed genes and the affected biological processes. These data are combined with clinical measurements in the mice including body weight, total cholesterol and HDL levels, blood glucose levels and response in the glucose tolerance test. Moreover, we are investigating the role of FOXO1 in the pathogenesis of the MetS. FOXO1 is a transcription factor with important roles in glucose and lipid metabolism in the liver. More specifically, we are generating ApoE3Leiden.CETP mice expressing small interfering RNAs against the mouse FOXO1 gene in the liver using adeno-associated virus (AAV)-mediated gene transfer and use these mice for transcriptomics analyses. Given that FOXO1 activity is under negative control by insulin, this genetic intervention is anticipated to ameliorate the clinical phenotypes of MetS. Our ultimate goal is to identify key genes that are implicated in the pathogenesis of the MetS and utilize this information for the development of novel biomarkers and therapies.