14. Investigating the molecular pathways regulating the expression and translation of phospholipase C zeta (PLCζ) in fertile and infertile human males.
The development of a mammalian embryo is initiated by a sequence of molecular events collectively referred to as ‘oocyte activation’.
Investigating the molecular pathways regulating the expression and translation of phospholipase C zeta (PLCζ) in fertile and infertile human males
The development of a mammalian embryo is initiated by a sequence of molecular events collectively referred to as ‘oocyte activation’. These mechanisms are critical in releasing the oocyte from meiotic arrest, recruiting maternal RNA, blocking polyspermy, and inducing gene expression/protein translation in the early embryo. These vital processes are regulated by the release of intracellular calcium into the ooplasm from the endoplasmic reticulum, manifesting as a series of calcium oscillations (of a species-specific amplitude and frequency), which cease around the time of pronuclear formation. These oscillations are critical in activating the oocyte and initiating the early phases of embryogenesis, and are translated to physiological responses/actions via calcium-sensitive transcription factors.
It follows that any perturbation in this vital sequence of events will most likely lead to a sub-fertile or infertile state. Over the last decade, phospholipase C zeta (PLCζ), a sperm protein introduced into the oocyte upon gamete fusion, has gained universal acceptance as the sperm protein factor responsible for initiating oocyte activation upon gamete fusion. A large body of consistent and reproducible evidence, from both biochemical and clinical settings, confers significant support for the role of PLCζ in this fundamental biological context, which has significant ramifications for the management of human male infertility. However, we know very little about the specific molecular mechanisms controlling the transcription and translation of this key protein.
This project (subject to funding) will investigate a range of potential regulatory mechanisms associated with the PLCζ gene such as the promoter and the potential roles of intronic sequences, mutations and single nucleotide polymorphisms.
The project offers training in a wide range of topics including those applicable to both clinical research and general personal development. The DPhil candidate will be trained in semen analysis, immunocytochemistry, quantitative PCR, micromanipulation, and bioinformatics.
The project represents a collaborative venture with Oxford Fertility and a range of other fertility units, both in the UK and overseas.
Dr Kevin Coward