The overall goal of my proposal is to identify means for improving β-cell regeneration in the adult pancreas. We previously developed a transgenic model of inducible total or partial β-cell ablation (termed RIP-DTR). We have reported that in these mice there is spontaneous reconstitution of new β-cells from heterologous (i.e. non-β) cells after near-total β-cell loss.

The RIP-DTR model has revealed an unsuspected degree of cellular plasticity in the pancreas of juvenile and adult mice, including aged individuals, regarding the spontaneous inherent capacity of islet a-cells to switch to insulin production upon β-cell loss.

During the next years we want to address the following fundamental questions:

1. What is (are) the signal(s) driving a-cell reprogramming upon near-total β-cell ablation?

2. Can the a-to-β-cell conversion be fostered? Why only a small fraction of a-cells engages into conversion? What is the nature of the epigenetic modifications in reprogrammed a-cells?

3. Can human a–cells reprogram to insulin production?

4. What is the influence of ageing on islet cell plasticity?

5. Can other islet cells, i.e. besides a-cells, reprogram to insulin production?

6. Can in vivo a-cell conversion be facilitated by means of compounds mimicking the effect of instructive signals?

7. Are human islets endowed with cell plasticity capabilities? How diabetic conditions influence i) the capacity of human/mouse a-cells to reprogram, and ii) the maintenance of the β-cell phenotype?