Acinar cell plasticity in the adult mouse pancreas (ACINPLAST)
Acinar cell plasticity in the adult mouse pancreas
Start date: 01 Nov 2007,
End date: 31 Oct 2009
"Cellular metaplasia may occur by transdifferentiation of one mature cell type into another, sometimes via an intermediate state of dedifferentiation. This type of cellular plasticity seems to be found in adult pancreatic acinar cells. The loss of differentiation may turn the acinar cells in facultative stem cells in the adult pancreas. Both in regeneration of exocrine as well as endocrine tissue and in pancreatic disease states, this type of acinar-derived precursor cells has found to be implicated. Therefore, the different steps in acinar cell transdifferentiation and the signalling pathways and molecular mechanisms governing the process need to be investigated in depth. Before, we have developed an in vitro system to dissect different steps in acinar cell transdifferentiation starting from purified mouse acinar cells. This system permits to accurately evaluate changes in gene and protein expression during the different stages of acinar cell transdifferentiation, and when perturbing specific signalling mechanisms (using chemical inhibitors, RNA interference or using cells from genetically modified mice). Our study will be focused on Notch and Ras signalling events, and the role of caveolae as a higher hierarchical platform to integrate these signalling pathways. Results will be further validated in an in vivo experimental model of acino-to-ductal transdifferentiation, based on ligation of pancreatic ducts. We will also investigate a possible molecular switch of RBPs (recombining binding protein suppressor of hairless RBP-Jk and its paralogue RBP-L) and the genes targeted by it, when the cultured acinar cells convert into precursor-like cells. Knowledge on acinar cell plasticity can be used to prevent acinar cell de- and transdifferentiation in pancreatitis and pancreatic cancer, and can exploited for forced transdifferentiation towards endocrine beta-cells."
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