Preventing aneuploidy in oocytes; mechanisms, markers and their potential use in clinic

Currently 15% of couples are infertile, largely as a result of an error that originates in women when the immature oocyte divides to produce an egg. Many couples now rely on IVF to have children. However, this is often a long, distressing and expensive procedure that does not always produce a live birth. We aim to relieve these pressures by developing treatment strategies that will significantly improving IVF success rates. In a perfect division, the oocyte aligns all of its chromosomes accurately so that they may be divided equally between the future egg, and a much smaller polar body which is a waste product of this division. Unfortunately, this process fails frequently in human oocytes and eggs are often produced with an incorrect number of chromosomes, a condition known as aneuploidy. This error is the primary genetic reason for failed pregnancy, miscarriage and babies born with developmental disabilities. Indeed, nearly half of all miscarriages are aneuploid. In complete contrast to human oocytes, the equivalent division is not error prone in young mice and the majority of their oocytes divide normally, producing perfect eggs. My previous research has identified the existence of a mechanism which acts in the mouse oocyte to prevent aneuploidy. I now wish to understand how this mechanism, and other related mechanisms act, so that we may determine why human oocytes are let down through these processes. This information will be of significant benefit to the treatment of infertility. To achieve this, my team will uncover the molecular basis of key interactions between proteins involved in preventing aneuploidy in mouse oocytes. Following this we will use a novel, cutting edge technology to measure the levels of many proteins involved in regulating cell division in single oocytes. This will be carried out in both mouse oocytes and in human oocytes and will uncover how the balance of these proteins changes in populations of oocytes that commit frequent errors. This information has the potential to identify ways in which we may alter the protein balance in human oocytes so that they are less likely to produce aneuploid eggs, improving IVF success rates. Using mouse oocytes, we will take this a step further, only analysing the protein content of the oocytes waste polar body while fertilising the egg. By this method we can score resulting embryos for a number of indicators of health and directly relate this score back to protein content of the polar body. This strategy will identify protein markers of oocyte viability in polar bodies and, will pave the way to developing this strategy for use in human IVF, providing a quick and cost effective way for IVF clinicians to select the embryo most likely to produce a healthy baby. This research is important for the following reasons: - The UK spends ~£350,000,000 per year on 70,000+ rounds of IVF, these numbers are increasing. - Even in younger women, most will undergo at least 3 cycles of IVF before a live birth, this number is often many more. - Clinical depression, grief, anxiety-related illness, and relationship problems and are all firmly associated with infertility and its treatment. Indeed, psychological symptom scores in female patients suffering infertility are equivalent to other chronic medical conditions such as cancer. Taking into account the factors above, even modest improvements, either by improving success rates, or by allowing women to make earlier choices, will have enormous, global impact.