Cell cycle regulation in oocytes: can we prevent chromosome division errors that result in infertility and miscarriage?

背景准确的细胞分裂依赖于所有染色体的排列，以便它们平等地分离成两个新的子细胞。不幸的是，哺乳动物卵母细胞经常在染色体正确排列之前分裂，产生染色体数量异常的卵子。在人类中，这是导致妊娠失败、流产和婴儿发育障碍的头号遗传原因。与其他类型的细胞分裂相比，我们对哺乳动物卵母细胞的细胞周期调控知之甚少。因此，了解为什么一些卵母细胞失败而另一些进展对于每年接受IVF的70，000多名英国患者至关重要。目标和实验方法。平均而言，需要6个IVF周期才有更大的机会生孩子。本项目的目的是了解卵母细胞分裂过程中正确的细胞周期调控，并利用这些信息来鉴定有能力或无能力卵母细胞的细胞周期蛋白标志物。（较低和较高频率染色体分裂错误的优秀模型），学生将通过一种称为成像质量细胞仪（IMC）的单细胞技术来监测约30种参与细胞分裂的关键蛋白质的时空调节。在此之后，他/她将使用活卵母细胞，使用荧光蛋白表达，蛋白质敲除和共聚焦显微镜等技术，充分表达不同的蛋白质。最后，将有机会操纵关键蛋白质水平，旨在“拯救”否则将面临分裂错误风险的卵母细胞。新奇性和及时性。这个学生奖学金项目既非常新颖又及时，它利用了该领域的重大进展（我自己今年早些时候的出版物）和尖端技术来解决影响越来越大的全球问题。目前有15%的夫妇患有不孕症，英国每年在IVF上的花费超过3.5亿英镑。以前，两个主要因素限制了卵母细胞的细胞分裂研究。首先，缺乏证据证明哺乳动物卵母细胞中细胞周期调控的不同，其次，材料的困难性质。然而，我最近发表的（和未发表的）维康奖学金研究改变了目前关于卵母细胞细胞周期调控的教条，IMC的快速进化现在将允许从每个卵母细胞获得前所未有的信息水平。重要的是，我有初步的数据证明了这项技术首次在卵母细胞中的应用。

Background. Accurate cell division relies on the alignment of all chromosomes so that they segregate equally into two new daughter cells. Unfortunately, mammalian oocytes often divide before their chromosomes are properly aligned, producing an egg with an abnormal number of chromosomes. In humans this is the number one genetic reason for failed pregnancy, miscarriage and developmental disabilities in babies.When compared to other types of cell division, we know relatively little about cell cycle regulation in mammalian oocytes. Therefore, understanding why some oocytes fail and others progress is of critical importance to the 70,000+ UK patients undergoing IVF each year. Objectives and Experimental Approach. On average, it takes 6 cycles of IVF to have a greater chance of having a baby than not. The objective of this project is to understand correct cell cycle regulation in oocyte cell division and, to use this information to identify cell cycle protein markers of either competent or incompetent oocytes.Using the oocytes of younger and older mice (excellent models of lower and higher frequency chromosome division errors), the student will monitor the temporospacial regulation of ~30 key proteins involved in cell division by a single cell technology known as imaging mass cytometry (IMC). Following this, he/she will use live oocytes to fully characterise proteins that differ, using techniques such as fluorescent protein expression, protein knock down and confocal microscopy. Finally, there will be an opportunity to manipulate key protein levels, aiming to 'rescue' oocytes that would otherwise be at risk of committing division errors.Novelty and Timeliness. This studentship project is both highly novel and timely, its take advantage of a major advance in the field (my own publication earlier this year) and a cutting edge technologies to address a global problem of increasing impact. 15% of couples currently suffer infertility and the yearly UK spend on IVF is >£350,000,000. Previously, two major factors have limited cell division studies in oocytes. Firstly, a lack of evidence demonstrating how different cell cycle regulation is in mammalian oocytes, and secondly, the difficult nature of the material. However, my recently published (and unpublished) Wellcome Fellowship research changes the current dogma with regard to cell cycle regulation in oocytes and, the rapid evolution of IMC will now allow an unprecedented levels of information to be gained from each single oocyte. Importantly, I have preliminary data demonstrating the application of this technology for the first time in oocytes.