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

目前有15%的夫妇不孕，很大程度上是由于女性在未成熟的卵母细胞分裂产生卵子时发生的错误。现在许多夫妇依靠体外受精来生孩子。然而，这通常是一个漫长，痛苦和昂贵的程序，并不总是产生活产。我们的目标是通过开发治疗策略来缓解这些压力，这将显著提高试管婴儿成功率。在一次完美的分裂中，卵母细胞将所有的染色体精确地排列在一起，这样它们就可以在未来的卵子和分裂后产生的更小的极体之间平均分配。不幸的是，这个过程在人类卵母细胞中经常失败，卵子的染色体数量经常不正确，这种情况被称为非整倍体。这种错误是导致妊娠失败、流产和婴儿发育障碍的主要遗传原因。事实上，几乎一半的流产是非整倍体。与人类卵母细胞完全不同的是，在年轻的小鼠中，这种相等的分裂不容易出错，它们的大多数卵母细胞分裂正常，产生完美的卵子。我以前的研究已经确定了一种机制的存在，这种机制在小鼠卵母细胞中起作用，以防止非整倍体。我现在希望了解这个机制，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在这些过程中会下降。这一信息将对不孕症的治疗有重大的益处。为了实现这一目标，我的团队将揭示参与防止小鼠卵母细胞非整倍体的蛋白质之间关键相互作用的分子基础。在此之后，我们将使用一种新颖的尖端技术来测量参与调节单个卵母细胞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如何在频繁出错的卵母细胞群体中发生变化。这一信息有可能帮助我们确定改变人类卵母细胞蛋白质平衡的方法，从而减少产生非整倍体卵子的可能性，从而提高体外受精成功率。使用小鼠卵母细胞，我们将更进一步，在使卵子受精时只分析卵母细胞废极体的蛋白质含量。通过这种方法，我们可以对产生的胚胎的一些健康指标进行评分，并将该评分与极体的蛋白质含量直接联系起来。该策略将识别极体中卵母细胞活力的蛋白质标记，并将为开发用于人类体外受精的策略铺平道路，为体外受精临床医生选择最有可能产生健康婴儿的胚胎提供快速和经济有效的方法。这项研究很重要，原因如下：英国每年在7万多轮试管婴儿上花费约3.5亿英镑，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个周期的体外受精，这个数字通常要多得多。-临床抑郁、悲伤、焦虑相关疾病和人际关系问题，这些都与不孕症及其治疗密切相关。事实上，患有不孕症的女性患者的心理症状得分与其他慢性疾病（如癌症）相当。考虑到上述因素，即使是很小的改进，无论是通过提高成功率，还是通过允许妇女更早地做出选择，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.