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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055283-06
Application #
6630524
Study Section
Metabolism Study Section (MET)
Program Officer
Sato, Sheryl M
Project Start
1998-09-30
Project End
2006-06-30
Budget Start
2003-09-01
Budget End
2004-06-30
Support Year
6
Fiscal Year
2003
Total Cost
$294,502
Indirect Cost
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Lee, Seung-Hee; Hao, Ergeng; Kiselyuk, Alice et al. (2011) The Id3/E47 axis mediates cell-cycle control in human pancreatic ducts and adenocarcinoma. Mol Cancer Res 9:782-90
Kiselyuk, Alice; Farber-Katz, Suzette; Cohen, Tom et al. (2010) Phenothiazine neuroleptics signal to the human insulin promoter as revealed by a novel high-throughput screen. J Biomol Screen 15:663-70
Ball, Andrew J; Abrahamsson, Annelie E; Tyrberg, Bjorn et al. (2007) HES6 reverses nuclear reprogramming of insulin-producing cells following cell fusion. Biochem Biophys Res Commun 355:331-7
Itkin-Ansari, P; Marcora, E; Geron, I et al. (2005) NeuroD1 in the endocrine pancreas: localization and dual function as an activator and repressor. Dev Dyn 233:946-53
Itkin-Ansari, Pamela; Geron, Ifat; Hao, Ergeng et al. (2003) Cell-based therapies for diabetes: progress towards a transplantable human beta cell line. Ann N Y Acad Sci 1005:138-47
Demeterco, Carla; Itkin-Ansari, Pamela; Tyrberg, Bjorn et al. (2002) c-Myc controls proliferation versus differentiation in human pancreatic endocrine cells. J Clin Endocrinol Metab 87:3475-85
de la Tour, D; Halvorsen, T; Demeterco, C et al. (2001) Beta-cell differentiation from a human pancreatic cell line in vitro and in vivo. Mol Endocrinol 15:476-83
Halvorsen, T; Levine, F (2001) Diabetes mellitus-cell transplantation and gene therapy approaches. Curr Mol Med 1:273-86
Demeterco, C; Levine, F (2001) Gene therapy for diabetes. Front Biosci 6:D175-91
Halvorsen, T L; Beattie, G M; Lopez, A D et al. (2000) Accelerated telomere shortening and senescence in human pancreatic islet cells stimulated to divide in vitro. J Endocrinol 166:103-9

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