Deciphering the link between stress and regeneration in pancreatic beta cells

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The survival and normal function of cells depend on ubiquitously expressed signalling pathways that protect against proteotoxic and genotoxic stress as well as stress due to infection or inflammation. Among these pathways, the unfolded protein response (UPR) protecting against dangerous protein overload in the endoplasmic reticulum is especially important for highly active secretory cells. Pancreatic beta cells cope with variable metabolic insulin demand by constitutive and inducible engagement of the UPR. Recent results suggest that the UPR not only increases insulin folding and secretion capacity but can also induces beta cell proliferation through an unknown mechanism. We have found that deletion of a protease of beta cells upregulates the UPR and induces a strong proliferative response in murine beta cells. At the same time, non-obese diabetic mice deficient for such protease are protected from autoimmune diabetes, and their beta cells protected from T cell killing. The objective of this study will be to determine the underlying mechanism and signalling pathways and potentially identify targets for pharmacological modulation of stress responses. The project brings together highly complementary teams contributing i) a substantial set of preliminary data on mice and beta cells lacking such protease, ii) strong expertise on beta cell physiology and insulin processing, and iii) expertise in robotized small molecule screening approaches. In this project we will study the effect of deleting such protease on beta cell physiology, monitoring specifically insulin synthesis, processing and turnover using cell biological approaches. The objective of a second workpackage will be to analyse how the deficiency for this protease affects the innate and adaptive immune response to beta cells and specifically protects them from killing. Moreover, we will examine how absence of this protease triggers the UPR and how this is linked to beta cell regeneration, using cell biological, genomics and proteomics approaches. This will be studied both in murine and human beta cells. Finally we will employ a robotized screening to identify the signalling pathway mediating protection of cells lacking the protease of interest from proteotoxic stress. We anticipate that our project might help to elucidate how stress cannot only protect cells from damage, but also induce beneficial functional gains. In addition, we hope to identify pharmacological targets suitable for exploiting the protective potential of the UPR in beta cells and possibly other cells and tissues.