Understanding the molecular mechanisms that regulate beta cell mass have important ramification for fostering beta cell regeneration and the treatment of diabetes. We present data to show that the ability to expand beta cell mass declines with age and is correlated with reduced beta cell replication. We have begun to elucidate the molecular mechanisms responsible for age-dependent decline in the regenerative capacity of beta cells. In preliminary data we show that the Polycomb group genes Bmi-1 regulate the Ink4/Arf locus to limit the proliferative capacity of beta cells. Mice that lack Bmi-1 display diminished beta cell mass, hypoinsulinaemia and glucose intolerance due to premature senescence limiting the expansion of beta cell mass. Although decline in the capacity of beta cell to expand can be correlated with beta cell replication, we will assess which cellular compartment Bmi-1 acts to regulate beta cell mass expansion. We hypothesize that controlled targeting of Bmi-1 pathway could rejuvenate beta cells by extending their regenerative capacity. This enhancement in regenerative capacity could be harnessed to promote beta cell regeneration and expansion of beta cell mass in diabetic mouse models. We propose to investigate the role of age-dependent decline in beta cell replication in regulating beta cell expansion, mechanism by which Bmi-1 and other polycomb group proteins repress the Ink4/Arf locus and regulate beta cell replication and establish whether the Bmi-1 pathway can be targeted in cell-based therapies. Such an approach that exploits the mechanisms involved in the expansion of beta cell mass due to physiologic demands will be critical in developing novel therapeutic approaches that involve beta-cell regeneration in diabetic patients. PUBLIC HEALTH RELEVANCE: As diabetic patients require life-long insulin therapy and have a high risk of medical complications, preventative or curative therapies are urgently needed. Diabetes results from an inadequate mass of functional beta cells and there is increasing evidence to suggests that beta cell proliferation, the dominant means by which beta cells adapt to changing metabolic demands, is related to aging. This proposal contends that understanding the mechanisms of age-dependent beta cell expansion could be useful for regenerate beta cells and such an approach that exploits the mechanisms involved in the expansion of beta cell mass due to physiologic demands will be critical in developing novel therapeutic approaches that involve beta-cell regeneration in diabetic patients.