The long term goals of this study are to determine the molecular mechanisms that specify the development and differentiation of pancreatic exocrine tissue. Recent advances have been made concerning the developmental decision of a pancreatic progenitor cell to give rise to an exocrine versus endocrine cell fate. However, once the initial fate decision has been made, very little is known about the molecular events that direct exocrine differentiation. Currently, we are aware of only a single regulatory factor, p48, that is critically required for the generation of differentiated exocrine cells. As in many other developmental systems, the molecular mechanisms that direct the development and differentiation of the exocrine pancreas are likely to involve a complex network of regulatory factors. We have recently determined that Gata4, a transcriptional regulatory factor known to be essential for embryonic heart development, is expressed in the region of the foregut endoderm that gives rise to pancreas and later becomes restricted to the exocrine acinar and ductal epithelial cells. We hypothesize that Gata4 plays an important role in the differentiation and development of the exocrine pancreas. To test this hypothesis, we propose to further characterize the expression of Gata4 during embryonic pancreas development and determine its function in the development and differentiation of the exocrine pancreas. The specific aims of this R21 application are to: 1) Define the gene expression pattern of Gata4 in the developing exocrine pancreas. We will determine precisely when and where Gata4 is expressed in the embryonic pancreas and compare its expression patterns to known pancreatic molecular markers; 2) Identify and characterize the function of Gata4 in exocrine pancreas development. We will use antisense techniques in primary cell cultures and AR42J cells to examine the effects of loss of Gata4 on the development of the exocrine pancreas. We will also determine the ability of Gata4 to regulate known exocrine genes that contain Gata binding sites in their promoter regions; and 3) Identify Gata4 interacting factors in the exocrine pancreas by testing interactions with known pancreatic proteins, such as p48 and FTF, and screening for novel exocrine-specific interacting factors that impart exocrine-specific function on Gata4.

R21DK061151

2001-09-30

2003-08-31