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

目前有15%的夫妇不育，这在很大程度上是因为女性在未成熟的卵母细胞分裂产生卵子时犯了一个错误。许多夫妇现在依靠试管受精来生孩子。然而，这通常是一个漫长、痛苦和昂贵的过程，并不总是产生活产。我们的目标是通过开发显著提高试管受精成功率的治疗策略来缓解这些压力。在完美的分裂中，卵母细胞精确地对齐所有的染色体，这样它们就可以在未来的卵子和一个更小的极体之间平均分配，而极体是这种分裂的废品。不幸的是，这一过程在人类卵母细胞中经常失败，卵子产生的染色体数量经常不正确，这种情况被称为非整倍体。这一错误是导致妊娠失败、流产和出生时发育障碍的婴儿的主要遗传原因。事实上，近一半的流产是非整倍体的。与人类卵母细胞完全不同的是，同样的分裂在幼鼠身上不容易出错，它们的大多数卵母细胞正常分裂，产生完美的卵子。我之前的研究已经确定了在小鼠卵母细胞中存在一种防止非整倍体的机制。现在我希望了解这个机制以及其他相关机制是如何起作用的，这样我们就可以确定为什么人类卵母细胞通过这些过程被释放。这些信息将对不孕症的治疗有很大的好处。为了实现这一目标，我的团队将揭示与防止小鼠卵母细胞非整倍体有关的蛋白质之间关键相互作用的分子基础。接下来，我们将使用一种新的、尖端的技术来测量参与调节单个卵母细胞分裂的许多蛋白质的水平。这将在小鼠卵母细胞和人类卵母细胞中进行，并将揭示这些蛋白质的平衡是如何在经常出错的卵母细胞群体中发生变化的。这些信息有可能确定如何改变人类卵母细胞的蛋白质平衡，使其不太可能产生非整倍体卵子，从而提高试管受精成功率。使用小鼠卵母细胞，我们将更进一步，只分析卵母细胞在受精卵子时废弃极体的蛋白质含量。通过这种方法，我们可以对结果胚胎的许多健康指标进行评分，并将这一评分与极体的蛋白质含量直接联系起来。这一策略将识别极体中卵母细胞活性的蛋白质标记物，并将为开发这一策略用于人类体外受精铺平道路，为试管受精临床医生选择最有可能产生健康婴儿的胚胎提供一种快速且经济有效的方法。这项研究之所以重要，是因为以下原因：-英国每年在7万多轮试管受精上花费3.5亿GB，这些数字还在增加。-即使在年轻女性中，大多数人在活产前至少要接受3个周期的试管受精，这个数字往往要多得多。-临床抑郁、悲伤、与焦虑相关的疾病和关系问题，都与不孕不育及其治疗密切相关。事实上，患有不孕症的女性患者的心理症状评分与癌症等其他慢性疾病的评分相当。考虑到上述因素，即使是轻微的改善，无论是通过提高成功率，还是通过允许妇女更早做出选择，都将产生巨大的全球影响。

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.