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Insulin/IGF-1 Signaling Regulates Novel Activities of the ER Stress Response Gene ire-1

Ziel

The insulin/IGF-1 signaling pathway is a major conserved metabolic pathway that regulates aging and lifespan in worms, flies, and mammals. Using C.elegans as a model system, I discovered that ire-1, a highly conserved ER stress response gene, makes a big contribution to the longevity of animals with reduced insulin/IGF-1 signaling. I further discovered that inactivation of ire-1 results in a striking accumulation of DAF-28, an insulin-like peptide, in the body cavity of animals with reduced insulin/IGF1 signaling, but not in wild-type animals. ire-1’s most characterized mode of action is by activation of a downstream transcription factor XBP-1. A few recent studies have shown that ire-1 also has xbp-1 independent functions, however, these have not been characterized extensively. Interestingly, under conditions of reduced insulin/IGF-1 signaling, at least part of ire-1’s contribution to the extended lifespan is independent of xbp-1. Furthermore, the striking accumulation of the insulin-like peptide in the body cavity of animals with reduced insulin/IGF1 signaling is mediated by ire-1 completely independently of xbp-1. Thus, we identified novel xbp-1-independent activities of ire-1, which under conditions of reduced insulin/IGF-1 signaling alone, promote longevity and feedback to regulate insulin levels. I propose to combine molecular, genetic and biochemical approaches to further investigate the molecular mechanism that regulates the accumulation of the insulin/IGF-1 peptide, and investigate why this occurs specifically under conditions of reduced insulin/IGF-1 receptor signaling. These studies may be of particular importance and relevance in the context of diabetes, where insulin/IGF-1 signaling is dysfunctional, insulin levels are deregulated and insulin-secreting cells are over-loaded and suffer from ER stress.

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FP7-PEOPLE-2009-RG
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Koordinator

BAR ILAN UNIVERSITY
EU-Beitrag
€ 100 000,00
Adresse
BAR ILAN UNIVERSITY CAMPUS
52900 Ramat Gan
Israel

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Aktivitätstyp
Higher or Secondary Education Establishments
Kontakt Verwaltung
Estelle Waise (Ms.)
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