The Role of Nkx2.2 in Insulin and Ghrelin Cell Fates

University Of Colorado Denver, Aurora CO

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Abstract

DESCRIPTION (provided by applicant): Loss of insulin function or production leads to Diabetes Mellitus (DM). Currently, there is no cure for DM, though islet transplantation has proven to be promising treatment. Due to the scarcity of donor islets, however, studies are underway to differentiate insulin-producing cells from stem cell populations. Understanding normal transcriptional regulation of pancreatic development will be important for generating these surrogate insulin-producing cells. Nkx2.2, a transcription factor, is expressed in the earliest endocrine pancreas progenitor cells. Nkx2.2 null mice die perinatally, lack insulin-producing beta cells, and have increased ghrelin-producing epsilon cells. Ghrelin is an orexigenic hormone that is involved in metabolic regulation. The function and direct lineage of the ghrelin cells in the islet is still unknown. We hypothesize that ghrelin cells locally regulate insulin secretion in the islet and that Nkx2.2 may function as a binary switch in the beta cell and epsilon cell fate decision. To address these issues, the specific aims of the this study are: 1) Elucidating the lineages of the ghrelin cell and insulin cell fates with respect to Nkx2.2 using the tripartite "Tet On" system; 2) Determining the transcription factors involved in regulation of the mouse ghrelin promoter using luciferase assays, EMSAs, DMA footprinting, and in vivo transgenic promoter analysis; 3) Discover whether transgenic misexpression of Nkx2.2 in ghrelin cells induces a cell fate change from ghrelin to insulin cells.