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

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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.