Molecular and Cellular Basis for Beta Cell Therapy in Diabetes (OZR2414)

A reduction in the functional beta cell mass is a key feature of type 1 and type 2 diabetes. Strategies to prevent or cure diabetes hence require the timely preservation or restoration of a metabolically adequate and self-renewable beta cell population. To achieve this goal clinical interventions may consider to implant primary or bio-engineered beta cells, to stimulate beta cell neoformation in vivo, to enhance beta cell function by targeting stimulus-secretion coupling pathways, to protect residual beta cells from damage or death, or to modulate inflammatory or autoimmune mechanisms. These approaches may need to be combined: for instance, neoformed beta cells will be again the target of the immune system unless autoimmunity is arrested in type 1 diabetes. Indeed, until now no single approach has achieved a lasting cure/prevention of diabetes. During its 15-year collaboration the present network has studied molecular and cellular mechanisms implicated in beta cell replication, survival, death, adaptation and function, and their cross-talk with environmental factors and inflammatory/immune regulations, hereby identifying potential targets for clinical interventions and generating novel ideas for investigating additional mechanisms and new strategies. It has also developed state-of-the-art methods to measure functional beta cell mass in vivo and ex vivo, both in humans and in preclinical models and has established collaborations with (inter)national networks for basic research and clinical studies. The present application builds on this successful collaboration, and intends to measure functional beta cell mass at various ages and stages of inflammatory/immune activation in humans and animals with and without (pre)diabetes in order to identify cells and conditions that constitute or facilitate a self-renewable source of beta cells. It also builds on previous results to further dissect the influence of environmental diabetogenic factors (nutrients, pregnancy, viruses) on beta cell phenotype and signalling pathways involved in apoptosis, beta cell dysfunction and crosstalk with alpha cells, local inflammation, antigen presentation and replication.

Our working hypothesis is that - in order to develop a lasting cure for diabetes - novel beta cell therapies require a combined approach that not only secures or restores a sufficient beta cell function but also targets mechanisms that enhance beta cell protection and self-renewal. The present consortium has the necessary infrastructure, know-how, critical mass, preclinical models and access to patient and risk groups to identify new targets for intervention, to develop new combinatorial beta cell therapies and to translate them to the clinic.

Keywords:Cell Therapy, Prevention, Transplantation, Diagnostic Tests, Immunology, Cell Death and Survival, Islet Cell Pathology, Islet Cell Biology, Beta Cell Transplantation, Diabetes

Disciplines:Basic sciences, Biological sciences