The beta-cell mass is determined by the balance between the rates of beta-cell death (apoptosis) and the birth of new beta-cells (neogenesis). In the rat and mouse pancreas the beta-cell mass turns over approximately every 30 days (2-3%/day) due to apoptosis and the formation of new beta-cells as they differentiate from progenitor cells located in the pancreatic ducts. The applicant proposes a """"""""transcription factor hypothesis"""""""" as a cause of diabetes. This hypothesis states that specific transcriptional proteins, that regulate the expression of specific genes during pancreas development, are responsible for beta-cell neogenesis and apoptosis and that malfunctioning of these proteins may curtail beta-cell growth and function. The applicant has identified two such proteins involved in neogenesis: the homeodomain protein IDX-1 and the Pou-homeodomain protein Brain4 as key regulators of beta-cell and alpha-cell development, respectively. The intestinal incretin hormone glucagon-like peptide appears to stimulate the expression of IDX-1 and the neogenesis of beta-cells. We have also identified two bZIP (leucine zipper) proteins, C/EBPbeta and CHOP, that appear to participate in the apoptosis of beta-cells in cell culture models in vitro and by genetic manipulations of mice in vivo. The applicant believes that a fundamental understanding of how the expression of IDX-1, Brn4, C/EBPbeta and CHOP are regulated during pancreas development, islet cell neogenesis and apoptosis will provide opportunities for the development of future therapeutic approaches for the cure of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK055365-05
Application #
6635136
Study Section
Endocrinology Study Section (END)
Program Officer
Sato, Sheryl M
Project Start
1999-09-16
Project End
2007-06-30
Budget Start
2003-07-01
Budget End
2007-06-30
Support Year
5
Fiscal Year
2003
Total Cost
$273,720
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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Stanojevic, Violeta; Habener, Joel F; Thomas, Melissa K (2004) Pancreas duodenum homeobox-1 transcriptional activation requires interactions with p300. Endocrinology 145:2918-28
Abraham, Elizabeth J; Kodama, Shohta; Lin, Julia C et al. (2004) Human pancreatic islet-derived progenitor cell engraftment in immunocompetent mice. Am J Pathol 164:817-30

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