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Role of nuclear hormone receptors in determination of life span in Drosophila

Reference	BB/C51705X/1
Principal Investigator / Supervisor	Professor Linda Partridge
Co-Investigators / Co-Supervisors
Institution	University College London
Department	Genetics Evolution and Environment
Funding type	Research
Value (£)	345,790
Status	Completed
Type	Research Grant
Start date	01/05/2005
End date	30/04/2009
Duration	48 months

Abstract

Genetic and environmental interventions that extend lifespan are rapidly increasing our understanding of the ageing process. Both mutations in genes encoding components of the insulin IGF-like signalling (IIS) pathway and dietary restriction (DR) extend lifespan in distantly related organisms, including the nematode worm C. elegans, the fruit fly Drosophila and the mouse, suggesting that mechanisms of ageing are evolutionarily conserved. The power of the invertebrate model organisms with their short lifespan and completed genomes can therefore be brought to bear on the problem. The aim of the work outlined in the proposal is to understand the role of nuclear hormone receptors (NHRs), in the control of lifespan in Drosophila. Five of the 21 NHRs present in the Drosophila genome will be targeted for details study, based on (a) their known roles in determination of lifespan in Drosophila and C. elegans (b) the roles of related NHRs in mammals and (c) the complete phylogeny of the NHRs in the genomes of these two organisms and humans. Our unpublished work has shown that down-regulation of the ecdysone receptor (EcR) or its signalling partner ultraspiracle (USP) by double-stranded RNA interference (RNAi) in the adult nervous system is sufficient to extend female lifespan, as is RNAi and USP in the adult fat body. We propose to pursue the mechanisms by which EcR and USP extend lifespan. In C. elegans an NHR, DAF-12, is required for extension of lifespan by ablation of the germ line, and acts either in parallel to or downstream of IIS in extension of lifespan. The closest fly homologue of daf-12 is HR96, followed by EcR. In both C. elegans and Drosophila, orthologous winged helix forkhead transcription factors, DAF-16 in the worm and dFOXO in Drosophila, are key effectors in the IIS pathways and, when over-expressed, extend lifespan. A key interactant of FOXO in mammals is PPAR Gamma. In addition, PPAR alpha plays a role in control of xenobiotic metabolism, a process implicated in extension of lifespan. The closest fly homologues of PPARs are E75 and E78. We propose to determine the sites of activation of these 5 NHRs in the Drosophila adult, and to mis-express them there and determine the effects of lifespan and fecundity. Depending upon results, we shall determine the role of the ovary in extension of lifespan in females. We shall determine the role of these NHRs in resistance to multiple stresses, a frequent correlate of extension of lifespan in C. elegans, Drosophila and mouse. Finally, we shall investigate the role of the IIS pathway and DR in extension of lifespan by mis-expression of NHRs.

Summary

unavailable

Committee	Closed Committee - Genes & Developmental Biology (GDB)
Research Topics	Ageing, The 3 Rs (Replacement, Reduction and Refinement of animals in research)
Research Priority	X – Research Priority information not available
Research Initiative	X - not in an Initiative
Funding Scheme	X – not Funded via a specific Funding Scheme

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