Award details

A comparative analysis of Hsp90 and its possible role in drug resistance in nematode parasites

Reference	BB/E013473/1
Principal Investigator / Supervisor	Professor Eileen Devaney
Co-Investigators / Co-Supervisors
Institution	University of Glasgow
Department	Veterinary Infection and Immunity
Funding type	Research
Value (£)	437,716
Status	Completed
Type	Research Grant
Start date	01/11/2007
End date	30/04/2011
Duration	42 months

Abstract

Hsp90 is unique amongst the family of heat shock proteins because of the nature of the molecules with which it interacts. These include a variety of kinases and receptors which are essential for survival. Geldanamycin (GA), a compound which inhibits Hsp90 activity, has been widely used to define Hsp90 interactions and function. The free-living model nematode C. elegans is unique amongst eukaryotes in expressing a GA-resistant Hsp90. The first aim of this application is to investigate whether C. elegans is the exception or the norm amongst nematodes by analysing Hsp90 in a variety of important parasitic nematodes. Nematode parasites will be classified as GA-resistant or susceptible and amino acids associated with resistance identified and targetted for site directed mutagenesis. A transgenic line of C. elegans expressing mutated Hsp90 will be prepared and assayed for GA-susceptibility. The second aim of the grant is to investigate whether Hsp90 plays a role in drug resistance in nematodes. Here we propose to use C. elegans mutants that are resistant to anthelmintic compounds and determine whether a resistant phenotype can be modulated by compromising Hsp90 function. As there are an increasing number of small molecule inhibitors of Hsp90 becoming available, this study has the potential to offer a novel approach to restricting the spread of drug resistance.

Summary

Nematode parasites are round worms that infect humans and domestic animals. They can cause illness and a variety of symptoms in their hosts and are very important both economically in farm animals and in public health terms, particularly in poorer areas of the world. A major problem with nematode parasites of farm animals is the spread of drug resistance. There are three different types of drugs available to treat infected animals, but some nematodes are now resistant to all three classes of drug. In this study we will investigate whether a protein called Hsp90 is a good target for new drugs. This protein is of great interest in the field of cancer research and many new compounds are being prepared which inhibit its function. In addition we will test a hypothesis that Hsp90 might also be involved in drug resistance in nematodes. It has recently been shown to be very important in fungi that have become resistant to drugs and we will investigate whether it may have a similar function in nematodes. As there are many new inhibitors of Hsp90, this approach could offer the potential to reverse drug resistance.

Committee	Closed Committee - Animal Sciences (AS)
Research Topics	Animal Health
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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