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ARC Project

Title: "Discovery of the molecular pathways regulating pancreatic beta cell dysfunction and apoptosis in diabetes using functional genomics and bioinformatics" 

  • Decio L. Eizirik, MD, PhD (Coordinator)

    Laboratory of Experimental Medicine, Medical Faculty, ULB




  • Miriam Cnop, MD, PhD

    Division of Endocrinology, Department of Medicine, Erasmus Hospital

    Laboratory of Experimental Medicine, Faculty of Medicine, ULB

Funding: Communauté Française de Belgique 

Duration: 2010-2015 

Project overview: 
The two main forms of diabetes mellitus are type 1 and type 2 diabetes (T1D and T2D). They affect 30 million individuals in Europe, decreasing their life quality and expectancy. Of particular concern is that the prevalence of both forms of diabetes is increasing; it is expected to double in the next two decades. A reduction in functional pancreatic beta cell mass, caused by progressive loss of beta cell function and increased apoptosis, is a key component of both T1D and T2D. The molecular mechanisms underlying this decreased functional beta cell mass remain to be clarified. Molecular signaling in the beta cells is decisive for their survival or death in diabetes. We hypothesize that crosstalk between key gene networks and insufficient protective responses, due to inherent features of beta cells, trigger dysfunction and the apoptosis program. This crosstalk is modulated by the genetic background of the individuals at risk, but it is presently unknown how candidate genes for diabetes affect beta cell function and survival, and how they interact with environmental agents that may trigger disease, e.g. glucolipotoxicity in T2D and viral infections in T1D. Against this background, the aim of the present proposal is to utilize functional genomics and advanced molecular biology and bioinformatics tools to identify molecular signatures and pathways responsible for beta cell dysfunction and apoptosis in diabetes, and to use this knowledge to define novel targets for intervention to preserve beta cell mass.
Main objectives: 

  •  Identification of the gene signatures and regulatory molecular pathways that are responsible for the reduction of functional beta cell mass in diabetes, with focus on the mechanisms regulating cytokine-, double stranded RNA (dsRNA, a byproduct of viral infection)- and glucose- and lipid-induced beta cell apoptosis.
  •  Characterization of the role of candidate genes for diabetes at the beta cell level, including a detailed analysis of their impact on beta cell function and survival and on their interaction with cytokines, dsRNA and glucolipotoxicity in determining beta cell fate.
  •  Intervention in the signal transduction pathways identified above using genetically modified mice, viral vectors and small interfering (si) RNAs. This step should identify and validate targets to preserve functional beta cell mass in diabetes.

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