Understanding the mechanism by which mature endocrine cells develop from endocrine precursors is of great importance as it could lead to the development of an unlimited source of beta cells for cell transplantation therapies for diabetes. A goal of diabetes research has been to develop cell lines from the human endocrine pancreas that can be grown in unlimited quantities and induced to differentiate along the beta cell lineage resulting in glucose-responsive insulin secretion. During the past funding period, success was achieved in developing cell lines that are committed to either the delta or beta cell lineages. This proposal is focused on exploring the nature of that lineage commitment. of human pancreatic endocrine cell lines to either the delta or beta cell lineages. The central hypothesis of this proposal is that the differential lineage commitment of the cell lines reflects differences in the expression of transcription factors that are involved in the establishment and maintenance of mature endocrine cells. Initially, the mechanism by which the bHLH transcription factor NeuroD1 acts to repress somatostatin promoter activity in a delta cell line, resulting in a partial switch to the beta cell lineage, will be studied. Other transcription factors that have been identified as candidates for being involved in delta versus beta cell lineage commitment will be studied using retroviral vector-mediated gene transfer into human pancreatic endocrine cell lines. Genes that are differentially expressed in delta versus beta cell lines and that are downstream of transcription factors that are important in b-cell development will be ascertained using DNA microarray technology. Finally, a genetic screen will be undertaken to isolate genes that upregulate insulin promoter activity.
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