Science, Technology and Engineering

Department of Genetics Staff

Dr Warwick Grant

Background

The Nematode Functional Genomics laboratory, with Associate Professor Warwick Grant as head, is focussed on the development and application of tools to elucidate and manipulate gene function in parasitic nematodes of mammals. We use a combination of techniques, including genetic and molecular analysis of gene function in the free-living nematode Caenorhabditis elegans, genetic analysis of parasitic species (mostly parasites of sheep) and direct manipulation of gene expression in parasites. Much of this work is in collaboration with AgResearch Ltd and Landcare Research, both of which are Crown Research Institutes in New Zealand. The four main project areas of interest are:

1. Ecological genetics of drug resistance in parasites: Drugs that kill nematode parasites (anthelmintics) are the main means by which parasite infections of livestock and humans are controlled. In both cases, the major threat to effective control is the evolution of anthelmintic resistance in the target species. This is especially acute in the sheep industries of developed southern hemisphere countries (Australia, New Zealand and South Africa) and is an emerging problem for some human parasites (eg. Onchcerca volvulus, the causative agent of River Blindness). Work in this area aims to (a) elucidate the mechanisms of anthelmintic resistance by identifying the key genes under selection and (b) develop sensitive, molecular based, diagnostic tests for changes in the frequency of resistance alleles in treated populations. This work includes population genetic analysis of resistant and susceptible nematode isolates using a range of genetic markers and techniques, and the testing of candidate resistance alleles by transgenesis of C. elegans with these candidates.
2. Discovery and validation of targets for the development of novel anthelmintics: There has been a rapid increase in the number of expressed sequence tags (ESTs) from parasitic nematodes and, more recently, of genome sequences. Data mining of these resources for potential drug targets, combined with the application of RNA interference (RNAi) and expression of parasite targets in C. elegans, is being used to discover and validate putative new targets. This is followed by the development of assays suitable for compound screening against those targets that meet the validation criteria.
3. Nematodes as vectors for biological control: The brush tail possum (Trichosurus vulpecula) was introduced into New Zealand in the mid-1800s and is now the most important vertebrate pest in that country. We aim to test the ability of the possum parasite Parastrongyloides trichosuri, when genetically manipulated to express a transgene detrimental to possums (eg. encoding an immunocontraceptive antigen), to act as a vector for biological control. We have shown that it is possible to construct transgenic P. trichosuri, and that possums infected with these parasites mount an immune response against the antigen encoded by the transgene. This work also incorporates extensive fieldwork which aims to validate population models that explore the likely impact such a nematode may have on the New Zealand possum population.
4. Nematodes of the genera Strongyloides and Parastrongyloides have unusual life histories: they posses free-living and parasitic life cycles. In the Parastrongyloides, the choice between these alternative life cycles is determined by environmental cues and is recapitulated at the start of each generation, so that it is possible to maintain the species either as a free-living or as a parasitic nematode, and to switch between life cycles by manipulation of the culture conditions. We are taking advantage of this feature of P. trichosuri biology to identify the key genetic components of the switch and, with this as a model, to investigate the likely genetic steps required in the evolution of a nematode parasite from a free-living ancestor. We are using a combination of molecular techniques (EST and microarray analysis, qRT-PCR) to define the genes that are likely regulators of the switch.

Honours, post graduate and post-doctoral research projects in any of these areas are available.