Insulin signaling (IIS) regulates metabolism, growth, and environmental stress responses and influences longevity in multicellular organisms. Specialized endocrine cells (pancreatic b cells of vertebrates or insulin producing cells, IPCs, of Drosophila) produce Insulin-like peptides (ILPs) and thus systemically regulate a range of biological processes in several distinct IIP target tissues. A better understanding of how insulin production is regulated by environmental parameters is required for rational approaches to treat and prevent metabolic diseases that are caused by IIS dysregulation, such as diabetes. Preliminary studies by the sponsor have shown that the stress-responsive Jun-N-terminal Kinase (JNK) signaling pathway represses ILP expression in IPCs of Drosophila and thereby regulates IIS activity throughout the organism. These findings suggest the JNK pathway as a relay for metabolic responses to stress. It remains unclear, however, how JNK is activated in IPCs. This application proposes to investigate potential mechanisms of this activation. The experiments proposed in aim 1 will identify which of the JNK - activating kinases (JNKKKs) encoded by the Drosophila genome are required for IPC-specific JNK activation and Insulin regulation.
Aim2 intends to assess whether JNK activation in IPCs is initiated by oxidative stress directly or by hormones secreted from peripheral tissues. The experiments proposed in the first two aims will use a candidate approach to identify and characterize the role of potential regulators of JNK signaling.
In aim 3, in contrast, an unbiased genetic screen to identify novel regulators of JNK and Insulin production in IPCs is proposed.
All aims are based on genetic approaches using Drosophila and include transcriptional and metabolic analysis, as well as demographic analysis of mortality in populations of different genotypes exposed to a variety of environmental conditions. PUBLIC HEALTH REALEVANCE: The studies proposed here will assess the regulation of insulin production and physiology by stress signaling in an intact organism. Due to the evolutionary conservation of IIS and JNK signaling, as well as the functional analogy of IPCs and pancreatic b cells, it can be expected that the insight generated by studies in Drosophila will help to understand this regulatory system, its components, and its physiological and pathological impact on metabolic homeostasis and aging in vertebrates.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Postdoctoral Individual National Research Service Award (F32)
Project #
5F32DK083862-03
Application #
8012868
Study Section
Special Emphasis Panel (ZRG1-F06-E (20))
Program Officer
Castle, Arthur
Project Start
2009-01-01
Project End
2011-12-31
Budget Start
2011-01-01
Budget End
2011-12-31
Support Year
3
Fiscal Year
2011
Total Cost
$53,042
Indirect Cost
Name
University of Rochester
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Kapuria, Subir; Karpac, Jason; Biteau, Benoit et al. (2012) Notch-mediated suppression of TSC2 expression regulates cell differentiation in the Drosophila intestinal stem cell lineage. PLoS Genet 8:e1003045
Biteau, Benoit; Karpac, Jason; Hwangbo, Daesung et al. (2011) Regulation of Drosophila lifespan by JNK signaling. Exp Gerontol 46:349-54
Karpac, Jason; Younger, Andrew; Jasper, Heinrich (2011) Dynamic coordination of innate immune signaling and insulin signaling regulates systemic responses to localized DNA damage. Dev Cell 20:841-54
Biteau, BenoƮt; Karpac, Jason; Supoyo, Stephen et al. (2010) Lifespan extension by preserving proliferative homeostasis in Drosophila. PLoS Genet 6:e1001159
Karpac, Jason; Hull-Thompson, Julie; Falleur, Melody et al. (2009) JNK signaling in insulin-producing cells is required for adaptive responses to stress in Drosophila. Aging Cell 8:288-95