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

辅助生殖技术（ART，如体外受精及相关技术）是大多数不孕症的成功治疗方法。抗逆转录病毒治疗是昂贵的治疗方法，其中大部分费用与技术的相对低效率有关。这很大程度上是由于由此产生的胚胎的高死亡率。通常情况下，45-80%的ART产生的胚胎不能存活第一周。因此，任何单个胚胎成功分娩的机会都不高。近年来，胚胎存活率只有适度的增长。单个胚胎产生婴儿的几率很低，这意味着：(1)通常需要几个治疗周期；(2)超排卵用于使产生的胚胎数量最大化，从而积累不需要的冷冻胚胎；(3)通常移植一个以上的胚胎，导致多胎妊娠的发生率显著升高。早期胚胎的高死亡率似乎是体外受精的一个普遍特征，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移除的细胞，允许组织重塑，它也用于移除不可逆转受损的细胞。P53是一种蛋白质，它有能力“感知”细胞压力和损伤，并在压力严重时指导细胞凋亡。该项目将研究ART是否导致p53表达增加，以及p53表达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。研究人员在老鼠身上进行了实验，这些老鼠的p53基因及其调控蛋白的功能发生了突变。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抗逆转录病毒治疗后导致细胞凋亡的蛋白质。

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.