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  • Book
    Cecil Mayra Benitez.
    Digital2014
    The pancreas consists of hormone-secreting endocrine cells, zymogen-producing acinar cells, and bicarbonate-secreting duct cells. Understanding their respective development is essential for developing strategies to derive precious cell types such as insulin-producing [beta] cells for treatment of diabetes mellitus. This thesis explores pancreas development using a systems-based approach to discover regulators and biological gene sets that contribute to cell differentiation, lineage specification, and endocrine-cell maturation. In Chapter 2, we describe the use of cell purification to obtain rare cell populations such as pancreatic progenitors from the native mouse pancreas. We query the transcriptome of 12 cell populations and discover previously unrecognized gene sets or modules that influence duct-cell biology and endocrine maturation. Using a reiterative approach, we identify and prioritize transcription factor regulators and their co-regulated modules. Using appropriate mutant mice, we validate the role of four novel regulators (Prdm16, Runx1t1, Etv1, and Bcl11a) and their effect on endocrine development. In Chapter 3, we describe the use of a pancreatic sphere culture system that can be scaled to phenotypically assess the effect of novel regulators on endocrine development. Lastly, we conclude with a framework for building gene regulatory networks (GRNs) from expression-based data and literature mining. Our goal is that a more global view of pancreas development will provide a framework for understanding the diversity and dynamics of pancreas formation.