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Investigating the effects of novel AKT inhibitors on the insulin/IGF-1 like signalling pathway in C. elegans

Doyle, Kevin (2016) Investigating the effects of novel AKT inhibitors on the insulin/IGF-1 like signalling pathway in C. elegans. Master of Research (MRes) thesis, University of Kent,. (doi:10.22024/UniKent/01.02.59976) (Access to this publication is currently restricted. You may be able to access a copy if URLs are provided) (KAR id:59976)

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https://doi.org/10.22024/UniKent/01.02.59976

Abstract

Caenorhabditis elegans, a free-living nematode, has developed into an exciting model for the study of ageing. It has a lifespan of around three weeks and a number of evolutionarily conserved pathways that can be manipulated to extend its lifespan and healthspan. The best characterised of these pathways is the insulin/IGF-1 signalling pathway (IIS) with the FoxO transcription factor DAF-16 acting as the main target of the pathway. Inhibition of IIS results in the translocation of DAF-16 into the nucleus, allowing it to activate a host of target genes causing lifespan-extension and stress resistance to a wide range of different factors.

The aim of this study was to pharmacologically inhibit the IIS pathway using the ATP-competitive AKT inhibitors AZD5363 and AT14148, the allosteric AKT inhibitor MK-2206, the IGF1R inhibitor OSI-906 and the ROCK inhibitor GSK-269962. A C. elegans transgene strain possessing a DAF-16::GFP reporter in order to monitor localisation of DAF-16::GFP under a fluorescent microscope. Worms were treated with the compounds and scored for the nuclear localisation of DAF-16. A bus-8 strain of C. elegans with increased sensitivity to drugs was also used in the investigation. Preliminary findings suggest that MK-2206, AT1148 and GSK-269962 could be having an effect on DAF-16 nuclear localisation. Further studies are needed in order to clarify whether this nuclear localisation is due to inhibition of the IIS pathway or whether it is part of a stress response to high concentrations of the drug.

Item Type: Thesis (Master of Research (MRes))
Thesis advisor: Garrett, Michelle
Thesis advisor: Tullet, Jennifer M.A.
DOI/Identification number: 10.22024/UniKent/01.02.59976
Additional information: The author of this thesis has requested that it be held under closed access. We are sorry but we will not be able to give you access or pass on any requests for access. 23/09/2021
Uncontrolled keywords: Cell Biology, C. elegans, Ageing, AKT-inhibitors, DAF-16
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Users 1 not found.
Date Deposited: 20 Jan 2017 16:00 UTC
Last Modified: 23 Sep 2021 14:24 UTC
Resource URI: https://kar.kent.ac.uk/id/eprint/59976 (The current URI for this page, for reference purposes)
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