The repression of Insulin/IGF signaling (IIS) by stress signaling pathways is a central mechanism to promote stress tolerance and metabolic homeostasis in metazoans, extending lifespan. Recent studies in mouse progeria models demonstrate that DNA damage is an important stimulus for the systemic repression of IIS, and that this repression increases cytoprotective processes in insulin target tissues, serving as an adaptive mechanism. The mechanisms governing the repression of IIS by DNA damage remain unclear. The authors introduce a Drosophila model to address this question and propose that a network of endocrine signaling by inflammatory cytokines modulates IIS activity by regulating expression of insulin-like peptides in Insulin Producing Cells of the brain. This network is proposed to significantly influence tissue and metabolic homeostasis, as well as lifespan in the fly. To test this hypothesis and to explore the proposed signaling hierarchies, the authors propose genetic studies addressing the following questions: (i) Does release of inflammatory cytokines from stressed tissues repress Insulin signaling systemically by regulating Insulin-like peptide expression? (ii) Does signaling by NFkappaB-like factors regulate a secondary response that allows restoring Insulin activity after stress? (iii) Can a temporal and spatial sequence of endocrine signaling interactions that control the systemic response to DNA damage be characterized? (iv) Does the established endocrine signaling network regulate metabolic and proliferative homeostasis and longevity in aging flies? The proposed experiments are expected to provide important insight into the signaling network regulating insulin signaling in response to DNA damage and other stressful challenges in metazoans. These interactions are expected to be evolutionarily conserved and potentially influence stress tolerance and lifespan in vertebrates, while at the same time playing significant roles in promoting metabolic dysfunction under chronic inflammatory conditions, as observed in obese animals.

Public Health Relevance

Regulation of Insulin signaling activity by stress signaling is an important process that allows adaptation to environmentally stressful conditions. At the same time, this antagonism promotes insulin signaling defects observed in age-related metabolic diseases. The proposed project seeks to characterize the signaling interactions that govern metabolic and tissue homeostasis systemically and test whether such interaction influence metabolic health, tissue maintenance and longevity in the fly. The studies will be performed using Drosophila, a genetically accessible model organism with a long history of significant contributions to biomedical research.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG028127-08
Application #
8424990
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Velazquez, Jose M
Project Start
2006-06-01
Project End
2016-02-29
Budget Start
2013-04-01
Budget End
2014-02-28
Support Year
8
Fiscal Year
2013
Total Cost
$375,827
Indirect Cost
$182,102
Name
Buck Institute for Age Research
Department
Type
DUNS #
786502351
City
Novato
State
CA
Country
United States
Zip Code
94945
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Luis, Nuno Miguel; Wang, Lifen; Ortega, Mauricio et al. (2016) Intestinal IRE1 Is Required for Increased Triglyceride Metabolism and Longer Lifespan under Dietary Restriction. Cell Rep 17:1207-1216
Li, Hongjie; Qi, Yanyan; Jasper, Heinrich (2016) Ubx dynamically regulates Dpp signaling by repressing Dad expression during copper cell regeneration in the adult Drosophila midgut. Dev Biol 419:373-381
Adams, Peter D; Jasper, Heinrich; Rudolph, K Lenhard (2015) Aging-Induced Stem Cell Mutations as Drivers for Disease and Cancer. Cell Stem Cell 16:601-12
Deng, Hansong; Gerencser, Akos A; Jasper, Heinrich (2015) Signal integration by Ca(2+) regulates intestinal stem-cell activity. Nature 528:212-7
Ayyaz, Arshad; Li, Hongjie; Jasper, Heinrich (2015) Haemocytes control stem cell activity in the Drosophila intestine. Nat Cell Biol 17:736-48
Wang, Lifen; Ryoo, Hyung Don; Qi, Yanyan et al. (2015) PERK Limits Drosophila Lifespan by Promoting Intestinal Stem Cell Proliferation in Response to ER Stress. PLoS Genet 11:e1005220
Neves, Joana; Demaria, Marco; Campisi, Judith et al. (2015) Of flies, mice, and men: evolutionarily conserved tissue damage responses and aging. Dev Cell 32:9-18
Wang, Lifen; Zeng, Xiankun; Ryoo, Hyung Don et al. (2014) Integration of UPRER and oxidative stress signaling in the control of intestinal stem cell proliferation. PLoS Genet 10:e1004568
He, Ying; Jasper, Heinrich (2014) Studying aging in Drosophila. Methods 68:129-33

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