NEW IRE-1 ACTIVITY (256551)

  https://cordis.europa.eu/project/id/256551

  FP7 (2007-2013)

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

  Marie Curie Action: "Reintegration Grants" (FP7-PEOPLE-2009-RG)

  biomolecules  ·  diabetes  ·  mammalogy

  2010-04-01 Start Date (YY-MM-DD)

  2014-03-31 End Date (YY-MM-DD)

  € 100,000 Total Cost

  Description

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.

  Complicit Organisations

1 Israeli organisation participates in NEW IRE-1 ACTIVITY.