The long-term objectives of this proposal are to understand the function of mammalian Sir2 in the endocrine control of aging and longevity by the insulin/IGF-I system in mammals. Recent studies have demonstrated that insulin/IGF-I signaling pathways play critical roles in regulating the pace of aging and longevity in worms, flies and mice. Additionally, caloric restriction, which extends life span in a wide variety of organisms, reduces blood insulin and IGF-I levels in mammals. The Sir2 (silent information regulator 2) nicotinamide adenine dinucleotide (NAD)-dependent deacetylases have been demonstrated to link glucose metabolism to the mechanism of aging and longevity in yeast and C. elegans. We have found evidence that mammalian Sir2 plays an important role in regulating transcription in pancreatic beta cells. Based on our preliminary findings presented in this proposal, it is hypothesized that mammalian Sir2 controls glucose metabolism, aging and longevity by regulating transcription of specific genes required for the insulin-producing function of pancreatic b cells through its NAD-dependent deacetylase activity. This hypothesis will be addressed by the following specific aims: 1) examine insulin gene expression and insulin secretion in mouse primary islets infected with recombinant adenovirus carrying Sir2 cDNA or siRNA, 2) elucidate the molecular mechanism of mammalian Sir2-mediated transcriptional regulation by examining expression and modification of important transcriptional regulators in beta cells, and 3) examine the in vivo function of mammalian Sir2 in b cells by measuring multiple physiological parameters for glucose homeostasis in beta cell-specific Sir2 transgenic mice. These studies should provide a molecular framework to understand the function of mammalian Sir2 in beta cells, glucose metabolism and longevity control in mammals.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG024150-03
Application #
7091400
Study Section
Special Emphasis Panel (ZRG1-CMAD (01))
Program Officer
Fuldner, Rebecca A
Project Start
2004-09-01
Project End
2008-06-30
Budget Start
2006-07-01
Budget End
2007-06-30
Support Year
3
Fiscal Year
2006
Total Cost
$302,544
Indirect Cost
Name
Washington University
Department
Other Basic Sciences
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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