In mammals, there appears to be an intimate linkage between insulin signaling, life span, and fat storage. Reductions in insulin signaling promote excess fat storage, and obesity can result in insulin insensitivity. We use the nematode C. elegans to address our hypothesis that multiple conserved signaling pathways including TGF-2 and TOR, modulate insulin/IGF-1 signaling to coordinately regulate life span and fat storage. C. elegans possess an insulin/IGF-1 signaling pathway that is well conserved across species. Modulating this pathway leads to changes in life span and fat storage. Therefore, worms are an excellent system to determine how multiple pathways influence the insulin/IGF-1 signaling pathway for life span and fat storage regulation. To address our hypothesis we will perform the following three specific aims (1) We will dissect the cross talk between the TGF-2 and insulin/IGF-1 pathways (2) We will dissect the cross talk the TOR and insulin/IGF-1 signaling (3) We will identify phosphatases that regulate the Insulin/IGF-1 signaling pathway to modulate life span and fat storage. These phosphatases may regulate the insulin/IGF-1 signaling pathway or one of the multiple conserved pathways that couple the insulin/IGF-1 pathway. Over the long term, these studies should help to understand the complexities associated with diseases such as Type II diabetes.

Public Health Relevance

The insulin/IGF-1 signaling pathway is conserved across phylogeny. In this proposal, we dissect how additional conserved signaling pathways couple with the insulin/IGF-1 signaling pathway to cooperatively regulate life span and fat storage.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025891-09
Application #
8481483
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Finkelstein, David B
Project Start
2005-05-01
Project End
2015-05-31
Budget Start
2013-09-15
Budget End
2014-05-31
Support Year
9
Fiscal Year
2013
Total Cost
$306,312
Indirect Cost
$120,104
Name
University of Massachusetts Medical School Worcester
Department
Genetics
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Wang, Ping; Liu, Bin; Zhang, Delong et al. (2014) Imaging lipid metabolism in live Caenorhabditis elegans using fingerprint vibrations. Angew Chem Int Ed Engl 53:11787-92
Ritter, Ashlyn D; Shen, Yuan; Fuxman Bass, Juan et al. (2013) Complex expression dynamics and robustness in C. elegans insulin networks. Genome Res 23:954-65
Perrin, A J; Gunda, M; Yu, B et al. (2013) Noncanonical control of C. elegans germline apoptosis by the insulin/IGF-1 and Ras/MAPK signaling pathways. Cell Death Differ 20:97-107
Tissenbaum, Heidi A (2012) Genetics, life span, health span, and the aging process in Caenorhabditis elegans. J Gerontol A Biol Sci Med Sci 67:503-10
Yen, Kelvin; Narasimhan, Sri Devi; Tissenbaum, Heidi A (2011) DAF-16/Forkhead box O transcription factor: many paths to a single Fork(head) in the road. Antioxid Redox Signal 14:623-34
Narasimhan, Sri Devi; Yen, Kelvin; Bansal, Ankita et al. (2011) PDP-1 links the TGF-? and IIS pathways to regulate longevity, development, and metabolism. PLoS Genet 7:e1001377
Yen, Kelvin; Le, Thuc T; Bansal, Ankita et al. (2010) A comparative study of fat storage quantitation in nematode Caenorhabditis elegans using label and label-free methods. PLoS One 5:
Kwon, Eun-Soo; Narasimhan, Sri Devi; Yen, Kelvin et al. (2010) A new DAF-16 isoform regulates longevity. Nature 466:498-502
Narasimhan, Sri Devi; Mukhopadhyay, Arnab; Tissenbaum, Heidi A (2009) InAKTivation of insulin/IGF-1 signaling by dephosphorylation. Cell Cycle 8:3878-84
Padmanabhan, Srivatsan; Mukhopadhyay, Arnab; Narasimhan, Sri Devi et al. (2009) A PP2A regulatory subunit regulates C. elegans insulin/IGF-1 signaling by modulating AKT-1 phosphorylation. Cell 136:939-51

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