Functional genomic analysis of the role of p53 in early embryo death after assisted reproductive technologies (ART).

辅助生殖技术（ART，如IVF和相关技术）是大多数不孕症的成功治疗方法。ART是昂贵的疗法，其中大部分成本与技术的相对低效有关。这在很大程度上是由于所产生的胚胎的高死亡率。通常情况下，ART产生的胚胎中有45-80%不能在第一周存活。因此，任何单个胚胎成功分娩的机会都不高。近年来，胚胎存活率仅略有增加。导致婴儿的单个胚胎的低存活率意味着：（1）通常需要几个治疗周期;（2）超数排卵用于使产生的胚胎数量最大化，从而产生不需要的冷冻保存胚胎的积累;（3）通常转移一个以上的胚胎，导致多胎妊娠的显著发生率。早期胚胎的高死亡率似乎是IVF的一般特征，但其原因和影响因素尚不清楚。最近已经确定，它主要是由于一种称为细胞凋亡的细胞“自杀”形式而发生的。这种形式的细胞死亡具有重要的正常功能：它的激活允许不再需要被移除的细胞，允许组织重塑，并且它还用于移除不可逆损伤的细胞。p53是一种蛋白质，其具有“感知”细胞应激和损伤的能力，并且在应激严重时指导细胞进行凋亡。该项目将检查ART是否导致p53表达增加以及p53的升高是否导致胚胎细胞死亡。我们将研究控制胚胎中p53表达的因素。使用的是突变的小鼠，这些突变使p53及其几种调节蛋白的功能停止。实验将确定具有这些突变的胚胎的易感性，从而使我们能够确定ART后引起细胞凋亡的蛋白质。

Assisted reproductive technologies (ART, such as IVF and related techniques) are successful treatments for most forms of infertility. ART are expensive therapies and much of this cost is related to the relative inefficiency of the technology. Much of this is due to the high mortality of the resulting embryos. Typically, 45-80% of embryos produced by ART do not survive the first week. Consequently the chance of any individual embryo resulting in a successful birth is not high. There has been only modest increments in embryo survival in recent years. The low cahnce of individual embryos resulting in a baby means that: (1) generally several treatment cycles are required; (2) superovulation is used to maximise the number of embryos produced giving an accumulation of unwanted cryopreserved embryos; (3) more than one embryo is generally transferred resulting in a significant incidence of multiple pregancies. The high mortality of the early embryo seems to be a general feature of IVF but its causes and effectors are not known. It has recently been established that it largely occurs due to a form of cell 'suicide' known as apoptosis. This form of cell death has important normal functions: its activation allows for cells that are no longer required to be removed, allowing the remodelling of tissues and it also serves to remove cells that are irreversibly damaged. p53 is a protein that has the ability to 'sense' cell stress and damage and to direct the cell to undergo apoptosis if the stress is severe. This project will examine if ART cause increased expression of p53 and whether this elevation of p53 causes embryonic cell death. We will examine the factirs that control p53 expression in the embryo. using mice with mutations that stop the function of p53 and several of its regulatory proteins. Experiments will determine the susceptibility of embryos possessing these mutations and will therefore allow us to define the proteins causing apoptosis after ART.