Work package 4 of SUMMIT

Novel means to prevent diabetic complications are needed. An important mean in this undertaking would be to develop tools which would make development of novel drugs for prevention of complications more feasible. The SUMMIT consortium brings together European key leaders in the field of diabetes research; scientists with a deep insight into genetics, biomarker discovery, development of novel imaging assays for assessing progression of complications, novel animal models for chronic diabetic complications, in silico models to predict development of complications and response to novel treatments.

Our research group is involved in work package 4 of the SUMMIT consortium

Research on diabetic complications has been hampered by the limitation that most of the animal models used for T1D (NOD mice, BB rat) or T2D (db/db mice, GK rat) do not develop classical micro- and macrovascular complications. However, there are a few novel yet uncharacterized models from which we could gain important information. Therefore the first mission of WP4 is to characterize existing models for diabetic complications focusing on DN, DR and CVD. The following animal models are presently characterized: Akita mouse model, IGF-II/LDLR-/-ApoB100/100 mouse, BB/DR.LepR-/- congenic rats, PDGFBret/ret mouse (a.k.a. retention mouse), ZSF1 rats, DIO mouse, SUR1/E1506K x LDLR-/-ApoB100/100.

With the achieved background information of diabetic complications in existing and coming new models we will gain confidence in predicting the key pathological and pathogenic outcomes of interventions in clinical and intervention trials.

Partners: (1) Boehringer-Ingelheim Pharma GmbH Germany, (2) Lund University Sweden, (4) Karolinska Institute Sweden, (13) University of Kuopio Finland, (19) University of Turku Finland, (22) AstraZeneca AB Sweden, (23) Hoffmann-La Roche Switzerland, (25) Sanofi-Aventis Deutschland GmbH.

The final aim of WP4 is to create novel animal models for insulin resistance, T1D and T2D, and their micro- and macrovascular complications with special emphasis on nephropathy (DN), retinopathy (DR) and macrovascular disease (CVD). The generation of new models will be based on candidate genes identified in WP1 and/or WP2The consortium also aims to use knowledge from genetic and biomarker discovery programmes (in particular, novel pathway information) to support development of novel animal models, and includes European players with a strong track record in this area. The techniques will include generation of models featuring tissue-specific disruption of selected genes using Cre-loxP systems (in adipocytes, muscle, endothelium, pericytes and myocardium as required). SUMMIT will also generate animals in which alteration of gene function can be induced in later life: this will involve both conventional methods (using tetracycline and tamoxifen) as well as a novel lentiviral transgenesis technology which allows in vivo siRNA-knockdown of genes that would be embryonic lethal using conventional technologies. Apart from rodents, the consortium will have access to expertise (Tryggvason) in the use of zebra fish for rapid initial functional screening of genes with unknown functions. The animal models will provide a central bridge between the discovery projects and projects translating these findings into clinical settings.