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8 November 2016

PhD student Yvonne won best poster award at EASyM

Yvonne Rozendaal, PhD student at the TU/e won the prize for the best poster at the EASyM conference in Berlin, Germany.

best-poster-award-easym

 

20 July 2016

Happy Summer!

A nice summer to all RESOLVE participants!

 

7 June 2016

Clara John about her research

Worldwide 1.7 billion people are affected by supernutrition and its repercussion, outpacing the global burden caused by malnutrition (Haslam and James 2005; Rosen and Spiegelman 2014). In many cases obesity (BMI > 30 kg/m2), a consequence of overnutrition, is accompanied by a disturbance of the cellular and systemic cholesterol homeostasis. According to the National Institute of Health, USA this accounts for one of the ten major risk factors for cardiovascular diseases. One of the causes leading to atherosclerosis involves impairments in vascular metabolism of cholesterol rich lipoproteins (Lewington, Whitlock et al. 2007; Ference, Yoo et al. 2012).

Due to the high metabolic activity of brown adipose tissue (BAT) and the possibility to induce the browning of different white adipose tissue-depots, the activation of BAT is considered as a therapeutic target to treat or prevent metabolic diseases. One of the main functions of BAT is the non-shivering thermogenesis (Cannon and Nedergaard 2004) leading to an increase in energy expenditure, which is paralleled by a robust stimulation of appetite and food intake including cholesterol. Whereas glucose and fatty acids serve as fuels for energy production and can be metabolized directly (Cannon and Nedergaard 2004; Bartelt, Bruns et al. 2011, an excess of cholesterol intake needs to be disposed by alternative routes to avoid the systemic accumulation of potentially cytotoxic cholesterol.

The underlying hypothesis of my work is that cold induced BAT-activation results in a dynamic adaption of vascular lipoprotein- as well as cellular sterol metabolism to maintain the general regulation of systemic cholesterol handling.

Our studies showed that the BAT-activation resulted in an increased HDL-turnover as well as reverse cholesterol transport (RCT), the movement of cholesterol from peripheral tissues back to the liver via HDL. Those results support the‘HDL-Flux-Hypothesis’proposed by Rader and Tall (2012). The hypothesis suggests that therapeutic interventions to promote HDL-mediated cholesterol efflux to the liver will reduce cardiovascular risk, regardless of whether it affects plasma cholesterol levels (Khera, Cuchel et al. 2011; Rohatgi, Khera et al. 2014). Additionally, we could observe that activated BAT induces the hepatobiliary disposal of cholesterol in form of bile acids.

These findings lead to the assumption that the activation of BAT contributes to preserve systemic cholesterol homeostasis. Future studies should therefore address the question of whether the activation of brown and beige adipocytes in humans could serve as a therapeutic target to prevent cardiovascular diseases.

 

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.

 

 

11 January 2016

Prof. Bart Staels about RESOLVE

Bart STAELS, IPL, Lille – RESOLVE Partner 4

Leader of WP5 “Humanization of the computational model through the direct use of clinical data”

 

What is the expertise / knowledge that you bring into the RESOLVE project?

IPL brings expertise in transcriptional regulation of lipid and glucose metabolism, as well as in the cross-talk pathways between lipid and glucose metabolism, which is the primary topic of research in the RESOLVE project. IPL has developed expertise in the field of non-alcoholic fatty liver disease and its link with cardiovascular disease, amongst others via effects on atherogenic dyslipidemia. Moreover, IPL has expertise in the pharmacological modulation of these metabolic pathways by nuclear receptors.

The IPL laboratory, thanks to multiple facilities, has extensive expertise in transgenic mouse models, animal physiology, functional genomics and transcriptomics, cell culture and has active collaboration with clinical researchers.

What is your role in the RESOLVE project and why is your data relevant for the consortium?

The role of IPL is situated at two levels.

First, IPL is involved in ‘Longterm mouse experiments’ (WP4) by studying the role of activation of the hepatic nuclear receptor PPARalpha on lipid and glucose metabolism perturbations induced by atherogenic-dyslipidemic high fat/high sucrose/high cholesterol diets in apoE3Leiden CETP transgenic mice and wild type and PPARalpha-deficient mice. The data obtained will be useful in the verification of the model predictions.

Second, IPL is involved in the humanization and extension of the computational model by generating clinical data on overweight patients before (WP5; B Staels is the leader of WP5) and after interventions (diet, surgery, drug) (WP6). Bart Staels has an active collaboration with the clinician Luc van Gaal (Antwerpen, Belgium; UZA, RESOLVE Partner 9) since several years and established during the FP6 EU contract HEPADIP (2005-2010). IPL, together with UZA, have identified differentially expressed genes/pathways according to metabolic and liver status by transcriptomic analysis of liver biopsies (collected by UZA) from overweight and obese patients before (WP5) and after interventions (WP6). The transcriptomic analyses generate data that will be used in the genomescale metabolic model (GSMM), which is one of the modelling systems used in RESOLVE to connect lipid and glucose metabolism.

What are the challenges, in your opinion, in the project?

The challenges are to obtain a functional human relevant model, to better understand the connections between development of dyslipidemia/hyperglycemia/low HDL level and associated diseases (liver status) in the metabolic syndrome, but also to be useful for further fundamental research to identify new avenues to explore and/or to better understand these pathologies.

How can RESOLVE help your research?

RESOLVE is a scientific consortium that opens new opportunities of collaborations in the domain of lipid/glucose metabolism. Moreover, RESOLVE generates the possibility to correlate transcriptomic and metabolic data of the UZA human cohort, thus generating data for RESOLVE as well as new hypothesis which then need to be tested at the bench. The integration of biology expertises with mathematical modelling generated through RESOLVE is a major asset to advance our understanding of complex pathophysiological conditions. In this way, RESOLVE is truly unique.

How do you think, can system approaches help your research?

System approaches is an original approach, not readily exploited in biology laboratories such as IPL and thanks to RESOLVE this is now feasible. This recent and interesting strategy should allow the identification of new and unexplored ways in scientific projects in progress in the IPL laboratory.

How close is your science to the community and patients with the metabolic syndrome?

The research performed in the IPL laboratory combines basic research on preclinical models and cell culture models with translational approaches via collaborations with clinicians. Such collaborations with several clinicians who are specialists in the care of overweight and obese patients allows IPL to expand its translational approaches via access to patient tissues (liver, adipose tissue, intestine), allowing translation of results obtained from fundamental research to the patient level.

What are, in your opinion, directions of decisions that are vital to the progress of systems medicine?

One direction of research will be to study the impact of the environment, especially nutrition (ex: fatty acids), on the development/progression/regression of metabolic diseases for a better care of overweight/obese patients, in parallel to drug strategies.

 

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