NEW IRE-1 ACTIVITY

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

Coordinatore	BAR ILAN UNIVERSITY    more  Organization address address: BAR ILAN UNIVERSITY CAMPUS city: RAMAT GAN postcode: 52900 contact info Titolo: Ms. Nome: Estelle Cognome: Waise Email: send email Telefono: 97235317439 Fax: 97236353277
Nazionalità Coordinatore	Israel [IL]
Totale costo	100˙000 €
EC contributo	100˙000 €
Programma	FP7-PEOPLE Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
Code Call	FP7-PEOPLE-2009-RG
Funding Scheme	MC-IRG
Anno di inizio	2010
Periodo (anno-mese-giorno)	2010-04-01   -   2014-03-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	BAR ILAN UNIVERSITY  Organization address address: BAR ILAN UNIVERSITY CAMPUS city: RAMAT GAN postcode: 52900 contact info Titolo: Ms. Nome: Estelle Cognome: Waise Email: send email Telefono: 97235317439 Fax: 97236353277	IL (RAMAT GAN)	coordinator	100˙000.00

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 Obiettivo del progetto (Objective)

'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.'