(taken from the application) 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. Our general strategy is to identify proteins (transcription factors) that active cell-type-specific genes such as insulin in islet cells. These factors and their genes are then used as tools to understand the process of islet development and Beta-cell differentiation. In this proposal we focus on how the expression of islet transcription factor genes becomes restricted as the fetal pancreas develops. This restriction is a crucial, but poorly understood, determinant in the developmental patterning of the endocrine pancreas. We hypothesize that patterning of the developing endocrine pancreas has parallels to patterning events in neural development, and involves the intersection of cell intrinsic signals and cell extrinsic signals in the Notch pathway.
The specific aims of this proposal are to use transcription factor gene promoters, in vitro differentiation assays, and transgenic mouse models to test this hypothesis: 1. Identify the functionally important elements of the Nkx6.1 promoter that determine its activity in different cell types and at different stages of development. 2. Test the role of the Notch receptors and their ligands in the restriction of Nkx6.1 expression and endocrine patterning. 3. Test the role of the Numb and Numb-like proteins in blocking Notch signaling and permitting endocrine differentiation. The knowledge gained from these studies will illuminate the mechanisms underlying pattern formation in the developing pancreas. This information can eventually be applied to engineering new Beta-cells for patients with diabetes.
| Wilson, Maria E; Kalamaras, Julie A; German, Michael S (2002) Expression pattern of IAPP and prohormone convertase 1/3 reveals a distinctive set of endocrine cells in the embryonic pancreas. Mech Dev 115:171-6 |
| Lee, J C; Smith, S B; Watada, H et al. (2001) Regulation of the pancreatic pro-endocrine gene neurogenin3. Diabetes 50:928-36 |
| Smith, S B; Watada, H; Scheel, D W et al. (2000) Autoregulation and maturity onset diabetes of the young transcription factors control the human PAX4 promoter. J Biol Chem 275:36910-9 |
