CentRed · Centrosome Reduction: The elusive culprit behind unexplained male infertility?

Worldwide, 17% of couples are affected by infertility, with studies showing a steady decline in sperm quality over recent decades. One in three cases remain unexplained, often marked by a sudden loss of the early embryo due to erroneous cell division, and are therefore hard to treat. Case studies link early embryonic loss to defects in the sperm centrosome, a paternally inherited organelle essential for the embryo's first cell division. Unfortunately, a mechanistic understanding of sperm centrosome function is lacking and its contribution to (in)fertility is understudied. CentRed is centred on the hypothesis that the sperm centrosome is remodelled during spermatogenesis to organise the first embryonic cell division, via a pathway known as 'Centrosome Reduction', with many cases of centrosome-related infertility stemming from defects in this transformation. To test this hypothesis, my team and I will use a multi-disciplinary approach, combining in situ structural biology, histology and biochemistry. We aim to achieve the following objectives:1.In situ Structural Biology. Resolve the molecular changes that take place during Centrosome Reduction and visualise defects occurring in patients with centrosome-related infertility.2.Histology. Construct a comprehensive timeline of this molecular transition. 3.Biochemistry. Develop an in vitro assay to test and study sperm centrosome function in fertile and infertile male subjects. This pioneering work will be the first molecular study to resolve the fundamental role of the sperm centrosome and reshape our understanding of male-factor infertility. In a broader context, CentRed will result in new approaches to diagnose unexplained infertility and has the potential to vastly improve treatment outcomes.