Type 1 diabetes afflicts nearly three million Americans, many of which are children. The health care costs associated with treating this disease are staggerring: more than $10 billion. Type 1 diabetic patients are dependent upon insulin injections for life and are at constant risk for developing life-threatening complications. Excitingly, successful transplantation of pancreatic islets, which contain the insulin-producing beta cells, into diabetic patients resulted in short-term insulin independence. Unfortunately, widespread application of this promising cell replacement therapy is severely limited by the amount of available Islet donors. In efforts to overcome this shortage, several groups coaxed embryonic stem cells to fonn beta cells, but this process was very inefficient. Improving this directed differentiation process will require a better understanding of the molecular factors that coordinate beta cell differentiation in pancreatic development. The FGF10 growth factor is essential for the process of differentiating embryonic stems into the pancreatic beta cells. Our long-term objective focuses on how FGF10 functions In the developing pancreas. In normal pancreatic development, FGF10 induces proliferation of the pancreatic progenitor cells that generate all the cell types in the adult organ, including the beta cells. The target genes of FGF10 signaling in the pancreatic progenitors are poorly characterized. Our laboratory recently found that FGF10 signaling increases the expression of the p63 transcription factor In the pancreatic progenitor cells. The ability of p63 to stimulate proliferation of progenitor cells in other developing tissues suggests it has a similar function in the pancreas. To specifically address the function of p63 in the developing pancreas, the proposed project will examine the following: 1) define the spatial and temporal pattern of p63 expression in relation to other genes expressed during normal pancreatic development;ii) characterize the pancreatic developmental defects resulting from loss of p63 function;iii) determine which FGFIO-dependent developmental processes in the pancreas are mediated through p63. These goals will be accomplished using techniques, such as Immunohistochemistry, gain- and loss-of-function mouse models, histology, genomics analysis, confocal microscopy, and in situ hybridization. This project will significantly add to the knowledge about how p63 plays a role in the development of the pancreas. In addition, infonnation about p63's role in the pancreas will benefit researchers turning embryonic stem cells into beta cells as a cure for type 1 diabetes.
