Grant: Operating Grant

To date, the only successful approach for curing insulin-dependent diabetes is to replace the insulin-producing ß-cells that have been destroyed by disease. Pancreas and islet cell transplantation are promising therapeutic strategies; however, scarcity of transplantable tissue has limited their widespread adoption. One way to produce enough ß-cells to cure diabetes is to determine how the ß-cells develop normally within the embryo and apply this knowledge to the generation of ß-cells in the culture dish. This proposal focuses on a novel group of genes, known as microRNAs (miRNAs) that play important roles in the development of many tissues. MiRNAs function by binding to their targets and preventing them from being made into proteins. I have demonstrated that miRNAs control the formation of ß-cells but it's unclear how they do so. Here I hypothesize that a protein necessary during the formation of ß-cells called Sox9 is regulated by miRNAs. I have shown that Sox9 levels are lower when potential miRNAs regulators of Sox9 are present, at a critical time during development. Preliminary results also suggest Sox9 levels are elevated if miRNAs are not present during development. Here I propose the expansion of our understanding of the role of miRNAs in Sox9 regulation by answering three key questions: 1) Is Sox9 repression required for generating ß-cells? 2) Can miRNAs target Sox9 during ß-cell development? 3) Is regulation of Sox9 by miRNAs necessary for ß-cell development in both mice and humans? These studies will identify miRNAs that directly regulate Sox9 expression during ß-cell development. That knowledge will provide a better understanding of ß-cell formation and will assist in the development of methods for producing sufficient numbers of ß-cells to cure diabetes.