Investigation of the role of phospholipase C zeta during fertilization and in human infertility

Dr Parrington has played a prominent role in engaging with the public about science. He has written popular articles for The Guardian, the New Scientist, The Biologist, Chemistry in Britain, and Biological Sciences Review. He has written commissioned reports for the public about important scientific issues for the Royal Society, the Wellcome Trust and the British Council and selected the shortlist for the New Scientist/Wellcome Trust PhD student popular science essay competition for the last two years. He has given numerous talks about science for the public, most notably the Charles Darwin Award lecture at the British Association Science Festival in 2003. He has been involved in a number of initiatives to introduce school students to science organised by the Wellcome Trust. Thus he is very well placed to communicate future aspects of his research to the general public and explain its potential importance for medicine.

The primary focus of this proposal is to uncover the molecular mechanisms underlying a key developmental process ? the activation of the egg by the sperm at fertilization. Our previous work led to the important discovery that a novel sperm protein ? phospholipase C zeta (PLCzeta) ? appears to be to be the physiological agent of egg activation in mammals. This aims of this proposal are several fold. Firstly, it will uncover the mechanisms regulating the expression of PLCzeta in the testis and its localization and activation in the sperm and how this relates to its mechanism of action. To carry out these studies we will use an exciting new in vivo approach to studying sperm function, based upon gene transfer into the testis by electroporation, that we have recently shown allows us to express transgenes in mouse and hamster testis and sperm. Secondly, we will create partially defective mutant versions of PLCzeta in mouse and hamster sperm. These will allow us to dissect the mechanisms regulating its localization and its activation in the sperm, as well as its mechanism of action. We will use the resources of the mouse mutant archive at MRC Harwell as well using the in vivo gene transfer technique to express mutant and dominant negative forms of PLCzeta in mouse and hamster sperm. Thirdly, in a collaboration involving two IVF clinics, we will use a high throughput screening method to screen infertile male IVF patients in order to discover whether there is a link between defects in PLCzeta and certain types of human infertility. This proposal has great relevance for the diagnosis and treatment of infertility. It also has much commercial potential in its development of new ways to study gene function in the testis and sperm.