Archive for November, 2015

13 November 2015

Prof. Kardassis about his role in the RESOLVE consortium

 

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

 The expertise that I bring into the RESOLVE project is transcriptomics i.e. obtaining and analyzing RNA data from tissue samples in order to identify global changes in the expression profiles of genes and their association with certain human diseases. In RESOLVE, the disease in focus is the metabolic syndrome (MetS) i.e. a complex metabolic disorder consisting of multiples clinical features including obesity, type II diabetes and dyslipidemia. In our group, we are using the apoE3Leiden.CETP mouse model of MetS and we are performing genetic interventions in order to study the role of key transcription factors (proteins that are involved in the regulation of the expression of genes at the level of transcription) in the pathogenesis of the disease. Our ultimate goal is to use all this information in order to optimize the computational model of MetS that the RESOLVE consortium is developing and to identify novel biomarkers and possible therapeutic targets that will improve the prognosis, the diagnosis and the treatment of MetS.

 

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

 Human diseases are caused by dysregulation of the expression or the activity of genes. In monogenic disorders, the study of their molecular and genetic basis is a relatively easy task but for complex diseases such as the MetS which includes several co-morbidities, the role of specific genes in disease initiation, progression and resolution is not known. My role in RESOLVE is to provide information regarding the genes and gene networks which are involved in the various stages of the pathogenesis of MetS and how these are related to disturbances in other metabolic parameters.

 

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

 The challenges in the project are multiple. Perhaps the key challenge is how to integrate data obtained from different sources (human patients, mouse models) in a meaningful and useful way so that we understand better the pathology of the disease and develop novel diagnostic and prognostic tools. Another challenge is how to use standard operating procedures (SOPs) in an optimal way so that we minimize to the best possible degree the variability in the measurements between labs. Finally, a key challenge is how we will use all the information coming from different and complementary -omics approaches to further develop a comprehensive computer model allowing targeting the underlying mechanism of low HDL-C, high triglyceride and loss of glycemic control in MetS patients. This will hopefully be translated into novel avenues for development of therapeutic intervention.

 

 

How can RESOLVE help your research?

 RESOLVE is a highly multidisciplinary consortium consisting of teams with expertise in biochemistry, clinical chemistry, molecular biology, genetics, clinicians, biomedical engineers etc.  Through my participation at the RESOLVE consortium I have the opportunity to collaborate with all these people and exchange ideas, samples, technologies and data. Understanding complex diseases such as the MetS is a team effort and I am very fortunate to be part of this great team of investigators.

 

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

 In complex diseases such as the MetS which includes several co-morbidities, the role of specific genes in disease initiation, progression and resolution is not well known. It is anticipated that disturbances in genes encoding for transcription factors or signaling proteins will affect the expression and the activity of complex downstream gene networks and have a major impact on the pathogenesis of the diseases either in a positive or a negative way. The best approach to understand in depth MetS and to develop reliable diagnostic tools and therapies is through a systems approach only i.e. by applying large scale -omics approaches (proteomics, lipidomics, transcriptomics) that provide information not only on the expression of specific genes or the protein and lipid content at specific time points or conditions but also on how these patetrns are connected to each other in networks. RESOLVE has given me the opportunity to have access to large scale omics data from partner labs on one hand and at the same time the transcriptomics data that come out of our lab are accessible to the other partners for utilization and integration. I am anticipating that this team effort will be translated ino high impact joint publications and will open new avenues of research and new opportunities for funding.

 

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

 In my lab we are doing basic science i.e. we are trying to understand the molecular and genetic basis of human diseases such as the MetS at the molecular and cellular level. This information will subsequently need to be translated, in collaboration with clinical colleagues and the pharma industry, into novel treatments and therapies to the benefit of the patients. As basic scientists, we are not close to the patients but we are trying to disseminate the results of our research to the patient communities by giving seminars and writing articles in the local press.

 

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

  • Formation of systems (or translational) medicine “Centers of Excellence” in each country which will require joint investment (facilities and personnel) from EU and the government
  • More Horizon 2020 calls for systems medicine with the opportunity for renewal of successful proposals
  • Support for the development of novel computational tools for the translational utilization of systems medicine omics data
  • Development of strong European bioinformatics centers that will store and analyze the enormous amounts of new data coming from the labs

6 November 2015

Markus Heine (postdoctoral fellow) about his work in the RESOLVE project

My name is Markus Heine and I am a postdoctoral fellow at the University Medical Center Hamburg-Eppendorf (UKE) in the laboratory of Joerg Heeren. We aim to understand the systemic regulation of energy metabolism in health and disease states. Energy dense lipids are transported in the blood by special carriers that are called lipoproteins. We focus on the metabolism of a special class of lipoproteins, the triglyceride lipoproteins (TRL) that are produced from the liver as well as from intestinal cells after a lipid rich meal. Usually, TRL are processed by professional lipid handling organs, e.g. adipose tissue and muscle. These processes can be altered in disease conditions such as the Metabolic Syndrome in an organ-specific manner, changes that are often associated with the development of severe chronic diseases such as diabetes and atherosclerosis. In the EU project RESOLVE we try to understand the systemic disturbances in sugar and lipid metabolism observed in individuals with the Metabolic Syndrome. In my project, I am focusing on an adipose tissue that was just recently found to be active in adult humans, the brown adipose tissue (BAT). In contrast to white adipose tissue that stores energy in form of lipids, BAT burns lipids upon cold exposure to generate heat to defend the body against cold. Thus, the activation of BAT may be a good target to treat patients with obesity-associated diseases. To visualize and quantify the fate of lipoproteins under conditions of BAT activation, we have established several nanoparticle-based tools. These technologies are used to define the variables that influence the transport of TRL to their final destinations. One variable is the hormone insulin which is produced after a sugar digestion and mediates the uptake of sugars into different organs. We think that insulin also plays an important role for lipid uptake processes into activated BAT to fill up energy stores. Therefore, we used models to decipher the role of insulin under conditions mimicking the Metabolic Syndrome. The data generated in our laboratory are then used for a computer model called ADAPT, which at the end should help to predict disease development in individuals with the Metabolic Syndrome. Based on the ADAPT model the ultimate goal will be to identify individuals at high risk for the development of a specific, life-threatening disease allowing individualized prevention and treatment of obesity, atherosclerosis and diabetes.