To date, development of beta-cell replacement therapies for treatment of type 1 and type 2 diabetes is limited by the availability of pancreatic islets from organ donors. Hence, alternative strategies rely on generating and expanding beta-cells in vivo or in vitro from renewable sources such as adult progenitors or stem cells, which can be coaxed to differentiate into beta-cells. However, these strategies, based on the knowledge of in vivo embryonic beta-cell differentiation, are still inefficient. Therefore, a more comprehensive understanding of the signaling pathways required for beta-cell differentiation is necessary to make cell replacement therapies a feasible treatment strategy. Neurogenin3 (neurog3), the first transcription factor expressed in endocrine progenitors, is necessary and sufficient to induce endocrine differentiation. Thus, ectopic expression of neurog3 in cultured duct cells triggers the transcription factor cascade that initiates endocrine differentiation. However, little is known about the interplay between neurog3 and intercellular signaling pathways. The main aim of this proposal is to identify genes regulated by neurog3 that are also involved in intercellular signaling pathways and explore their function in endocrine and beta-cell differentiation. Starting from an ongoing study of neurog3 target genes in duct cells, this proposal will use a variety of molecular biology methods to generate a list of candidate genes based on their expression pattern during pancreas development. These molecules or other components of the pathway will be manipulated in vitro in cultured duct cells and pancreatic explants, and in vivo in mouse models to determine their role in beta-cell differentiation. This proposal will bring the applicant, an expert pancreas biologist, back to the EU where she will contribute with the expertise acquired in a third country to the field of beta-cell differentiation.
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