Objective: 1. To demonstrate that the normal growth mediator in other tissues, “cMyc”, is a safe and attractive molecule for human beta cell proliferation for Type 1 diabetes; 2. To elucidate the normal mechanisms that regulate cMyc-mediated human beta cell proliferation and expansion.3. To create human beta cell lines for research and drug development purposes.4. To allow three senior diabetes researchers to combine their expertise, to accelerate their progress.Background/RationaleThere are no current safe and effective mechanisms to drive human beta cell expansion, and there are no existing human beta cell lines that allow research, drug screening etc in human beta cells. To learn how to make human beta cells grow, we analyzed four standard rodent beta cell lines, and found that in each, there is common cell cycle “signature”: the same seven cell cycle molecules are activated. Asking what might be upstream of these, and driving the cells to proliferate, we found that one specific molecule, cMyc is mildly increased. This was surprising, because cMyc is believed by most beta cell researchers to induce beta cell death and de-differentiation or beta cell tumors. However, we found that introduction of low levels of cMyc into mouse, rat and human beta cells can drive them to proliferate, and does so without inducing cell death. Further, we found that low level cMyc introduction into the beta cells of transgenic mice does not injure them or cause tumors, but appears to cause a gradual increase in beta cell mass, as is desired in human diabetes. Finally, we have also shown that cMyc in collaboration with another protein called “ChREBP” works with blood glucose levels to regulate rodent and human beta cell growth. These considerations lead to three Specific Aims:1. (PI: Hebrok, Univ. California, San Francisco). To fully define the therapeutic and safety consequences of low level, physiologic expression of cMyc in the mouse beta cell in the pINS-cMycERTAM Transgenic Mouse. 2. (PI: Scott, Univ Pittsburgh). To define “upstream” therapeutic targets in the “Glucose, Glucokinase, Glut-1, -2, ChREBP, cMyc Pathway” using rodent and human beta cells. 3. (PI: Stewart, Univ. Pittsburgh). To develop continuously growing human beta cells for research and therapy. Anticipated OutcomeThese studies should demonstrate that: 1) there is a clear pathway involving cMyc that links glucose to multiple molecules within the beta cell to drive proliferation: many of these molecules should be attractive drug screening targets; 2) contrary to current belief, cMyc is a surprisingly attractive target for safely expanding human beta cell proliferation in vitro and in vivo; and, 3) it is possible to judiciously employ cMyc to develop continuously growing human beta cell lines for the first time, facilitating research in human, rather than rodent, diabetes. Relevance to T1DMAs outlined above.