Targeting organogenesis and beta cell survival: role of the lrh1/nr5a2-ptgs2/cox2 signaling axis in pancreatic islet physiology and pathophysiology

Type 1 Diabetes Mellitus (T1DM) is a disease caused by the selective destruction of pancreatic islet beta cells by aberrant activation of the immune system, characterized by a subsequent chronic unresolved proinflammatory status within the pancreas. Up to date, no effective therapies have been developed to cure this autoimmune disorder, which indeed, apart from the beta cell death and subsequent lack of insulin, leads to long-term complications that substantially impact on life quality and shorten life expectancy. However, our laboratory recently reported promising outcomes from the in vivo activation of a nuclear receptor, denoted as Liver Receptor Homolog 1 (also known as (a.k.a.) Nuclear Receptor Subfamily 5 Group A Member 2, LRH1/NR5A2), using different preclinical mouse models of autoimmune diabetes, and also in vitro, by mimicking the stress/proinflammatory conditions that characterize T1DM in both, mouse and human primary islet-cell cultures. These beneficial effects derived from the treatment with a chemical agonist of LRH1/NR5A2, codename BL001, which potentially favoured a crosstalk between the immune system and islet cells, aimed at protecting the beta cell mass via increasing its survival. Understanding the molecular signaling and consequences derived from LRH1/NR5A2 expression and activation in beta cells was the following step to exploit its therapeutic value within T1DM conditions. In this Thesis, we first uncovered the essential role of LRH1/NR5A2 expression in beta cells during neonatal development. We found that the LRH1/NR5A2 constitutive ablation in the beta cell mass caused a significant reduction of this cell type, mainly characterized by blunted proliferation, along with detrimental consequences in the metabolic and physical health of mouse pups that culminated in early death. We next demonstrated that the LRH1/NR5A2 specific activation in beta cells was the responsible of the beneficial effects observed in vivo, after BL001 treatment. Using a