The long-term objective of this laboratory is to understand the molecular mechanisms underlying the formation of the insulin-producing beta-cells in the pancreatic islets of Langerhans and to apply this knowledge to the replacement of the absent or defective beta-cells in patients with diabetes. We hypothesize that beta-cell fate determination requires the deviation of neurogenin3 expressing islet cell precursors from a default alpha-cell fate to a beta-cell fate. The genes involved in this process have not been identified. Our general strategy will be to work in collaboration with other members of the Program Project and the Beta Cell Biology Consortium to identify and to test genes that could be involved in the beta-cell fate decision.
The specific aims of this proposal are to identify genes involved in beta- cell fate determination: 1. Determine the pattern of genes expressed during the embryonic development of the pancreas. We will utilize the cDNA arrays available through the UCSF Mouse Genome Consortium to establish the global expression patterns of more than 15,000 mouse genes during pancreatic development. 2. Identify and characterize islet cell progenitors. In collaboration with the Bell lab (Project 1), we will utilize transgenic mice expressing fluorescent tags under the control of progenitor cell-specific promoters to purify pancreatic progenitor cells, to determine their ability to differentiate into different mature pancreatic cell types, and to analyze their gene expression patterns. 3. Determine the alterations of pancreatic gene expression in three genetic models of altered islet development: mice with disruption in the islet transcription factor Nkx6.1, Nkx2.2 and Lmx1.1 and mice with accelerated islet development caused by a neurogenin 3 transgene. 4. Test the role of identified genes in islet fate decisions using the fish, chick and mouse model systems and in humans in collaboration with the Stainer (Project 4), Hebrok (Project 3), and Bell (Project 1) labs. These experiments will provide a valuable resource for other members of the Beta Cell Biology Consortium while testing the hypothesis that specific genes deviate progenitor cells to a beta-cell fate during development.
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