Functional Genomics: Applications in Human Health, Animal Health and Crop Protection

David Sattelle, University of Oxford

November 17, 2009 @ 04:00 pm to 05:00 pm

100 Life Sciences Bldg (Berg Auditorium), Hershey CG623

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Dr. Sattelle is currently Professor of Molecular Neurobiology, University of Oxford and a Fellow of Wolfson College, Oxford._ He is being hosted by Dr. Peter Hudson, Director of The Huck Institutes of the Life Sciences at Penn State. Abstract In my laboratory we endeavour to exploit the wealth of new genome data, drawing on forward and reverse genetics, transgenic models, physiology and behaviour, to address problems in neurobiology. Functional genomics can yield useful information at the level of the genome and on genes, gene families and networks. The information derived from such studies can impact on human health, veterinary medicine and agriculture. Examples will be drawn primarily from the study of invertebrate genetic model organisms, the nematode worm, C. elegans and the fruitfly, D. melanogaster, although I will show how comparisons with other species can be instructive. Human health A transgenic worm over-expressing human ?-amyloid, a peptide important in Alzheimer s disease (AD) and Inclusion Body Myositis, is being subjected to a genome-scale RNAi screen to search for novel suppressors of amyloid toxicity. These data are compared to findings on new candidate AD risk factors from genome-wide association studies (GWAS) in order to discover which factors impact on amyloid toxicity. Novel arylamino-substituted diazine drugs, which inhibit amyloid aggregation and cellular toxicity, partially rescue the ?-amyloid-induced phenotype and are being optimised as potential therapeutic candidates. C.elegans models for congenital myasthenia syndrome and spinal muscular atrophy have also been developed along with automated phenotyping designed to facilitate chemical library screening of these nematode models of neurodegenerative and neuromuscular diseases. We have also begun to exploit to advantage the pharmacological differences observed between evolutionarily remote (C. elegans, human) nicotinic acetylcholine receptors (nAChRs), transmembrane molecules which mediate fast cholinergic signalling, with the aim of enhancing our understanding of human nAChR allosteric drug binding sites. Animal Health The nAChR gene family of C.elegans is among the largest and most diverse known. Nematode nAChRs are targets for several chemically-distinct classes of anthelmintic drugs. Chemistry-to-gene screening, based on levamisole, has identified all 5 subunits and key associated proteins of a major C. elegans body-wall muscle nAChR targeted by anthelmintics. Robust functional expression of distinct C. elegans nAChR subtypes has been achieved and, for the first time, a robust, functional recombinant parasite (Ascaris suum) nAChR has been generated, thereby opening the door to high-throughput, target-based, drug screening for novel anthelmintics acting on nAChRs. This development, together with automated behavioural monitoring of parasitic worms, will help accelerate the development of new anthelmintics with enhanced host tolerance. __ Crop protection Although among the smallest nAChR gene families, those of insects (e.g. fruitfly, mosquito, honeybee, flour beetle) are nevertheless highly diverse. This is the result of alternative splicing, RNA editing and the presence in the family of a highly divergent subunit group. Neonicotinoids, which play a major role in insect control worldwide, target insect nAChRs. The robust functional expression of recombinant insect nAChRs remains a challenge. However, hybrid recombinant nAChRs can be expressed, mimicking some key properties of native insect nAChRs, including neonicotinoid actions. Recent crystal structures of imidacloprid and clothianidin, bound to an invertebrate acetylcholine binding protein (AChBP) with similarities to nAChRs, offer further insights into neonicotinoid actions and may assist in the design of future control chemicals which target pest insects but spare beneficial insect species._ _____ References Nature (2006) 443, 931-49; Nature (2008) 452, 949-55; Nature Rev Drug Discovery (2005) 4,321-30; Genome Res (2006) 16, 1422-30; J Neurosci (2009) 29, 4287-92; PLOS Pathogens (2009) 5, e100517; Mol Pharmacol (2009) 76, 1-10; Pharmac Rev (2009) 61, 39-61; Human Mol Genet (2009) 18, 97-104. http://www.mrcfgu.ox.ac.uk. _

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