Background: Diabetes is a major health problem in United States of America. Despite extensive study, the exact causes of this disease are not known. However, evidence suggests that all forms of diabetes are associated with reduced beta-cell function and survival. Our laboratory has recently shown that insulin itself controls beta-cell survival. Objective of research: The goal of the proposed research is to characterize the mechanisms through which insulin regulates beta-cell survival in human and mouse islets. We hypothesize that insulin may promote beta-cell survival via a kinase called Raf-1. Description of research project: We will utilize molecular biology, live-cell imaging and knockout mice to dissect the role of Raf-1 in anti-apoptotic beta-cell insulin signaling. Relevancy to diabetes: We expect our proposed experiments to yield new mechanistic information regarding insulin as a beta-cell survival factor. Greater understanding of the control of apoptosis in human islets is crucial to prevent beta-cell death in all types of diabetes and to improve clinical islet transplantation.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
1F31DK079346-01X1
Application #
7475370
Study Section
Special Emphasis Panel (ZRG1-IMM-L (29))
Program Officer
Agodoa, Lawrence Y
Project Start
2007-08-01
Project End
2010-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
1
Fiscal Year
2007
Total Cost
$7,850
Indirect Cost
Name
University of British Columbia
Department
Type
DUNS #
251949962
City
Vancouver
State
BC
Country
Canada
Zip Code
V6 1-Z3
Alejandro, Emilyn U; Lim, Gareth E; Mehran, Arya E et al. (2011) Pancreatic ?-cell Raf-1 is required for glucose tolerance, insulin secretion, and insulin 2 transcription. FASEB J 25:3884-95
Alejandro, Emilyn U; Kalynyak, Tatyana B; Taghizadeh, Farnaz et al. (2010) Acute insulin signaling in pancreatic beta-cells is mediated by multiple Raf-1 dependent pathways. Endocrinology 151:502-12
Johnson, James D; Alejandro, Emilyn U (2008) Control of pancreatic beta-cell fate by insulin signaling: The sweet spot hypothesis. Cell Cycle 7:1343-7
Beith, Jennifer L; Alejandro, Emilyn U; Johnson, James D (2008) Insulin stimulates primary beta-cell proliferation via Raf-1 kinase. Endocrinology 149:2251-60
Alejandro, Emilyn U; Johnson, James D (2008) Inhibition of Raf-1 alters multiple downstream pathways to induce pancreatic beta-cell apoptosis. J Biol Chem 283:2407-17