This is a renewal application in response to RFA-DK-04-017 for a program that will explore the molecular and gene regulatory events that occur during pancreas development. To achieve the goal of creating a replenishable source of beta-like cells for transplant therapy of diabetic patients, it is necessary to understand the growth properties and cellular differentiation capacity of pancreatic precursor cells, and to be able to direct these cells towards a beta-cell phenotype. The goal of this program, which consists of four individual projects and one core (administrative), is to gain a deeper understanding of the gene regulatory processes that occur near the midpoint of murine pancreogenesis. We will create and characterize a variety of new mouse models in order to determine how different gene regulatory processes impact the fate of immature pancreatic progenitor cells. We expect that these studies will contribute to a better understanding of how beta-cell differentiation differs from that of other endodermal cell types. MacDonald will examine the interface of Notch-signaling and the key transcription factor PTF1a for resolving the islet versus acinar cell fate from common embryonic progenitors. Magnuson will use cassette exchange technology in mouse ES cells to better understand how the Delta/Notch signaling pathways affect both the multipotency and cell fate decisions of pancreatic progenitor cells. Stein will determine the special role that MafA plays to direct the expression of genes that define beta-cell identity. Wright will analyze the role of several key gene transcriptional networks, and how they affect endocrine cell differentiation within the pancreas.
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