Grant: Project Grant

Type 1 diabetes (T1D) is a devastating disease caused by the death of insulin-producing pancreatic beta-cells by our own immune system. There is no cure for T1D, and current treatment involves daily injections of insulin to keep blood glucose levels with a healthy range. It is generally thought that patients with long-standing T1D do not have any beta-cells, but numerous studies have now identified the presence of residual beta-cells. This raises the question of whether it is possible to coax these remaining beta-cells to expand in number, which would remove the need for daily insulin injections. Ultimately, this could represent an effective treatment for T1D. The pathways that control human beta cells proliferation are very complex, and they require precise and accurate actions of numerous proteins at specific times and places within the cell. Currently, the identity of factors that coordinate these proteins in the human beta-cell is not known, but specialized proteins called molecular scaffolds are logical candidates, as they coordinate the actions of proteins within cells and have the ability to control cell growth. Previously, we reported that molecular scaffolds belonging to the 14-3-3 protein family are essential for the regulation of metabolism, and they are important in regulating the survival and growth of mouse beta-cells. Mice lacking 14-3-3zeta in all cells have significantly higher numbers of beta-cells, in addition to better glucose control. This raises the question of whether one can specifically target 14-3-3zeta in human beta-cells to increase proliferation and treat diabetes. This will be tested by first determining the precise roles of 14-3-3 proteins in human beta-cells, followed by developing genetargeting approaches to reduce 14-3-3zeta function in human beta-cells to stimulate their proliferation. Ultimately, it is the over-arching goal of this proposal to see whether it is possible to stimulate the growth of human beta-cells to treat T1D.