Role Of Tumour Suppressor Genes In Early Embryopathy
Funder
National Health and Medical Research Council
Funding Amount
$408,000.00
Summary
Assisted reproductive technologies (ART, such as IVF and related techniques) are successful treatments for most forms of infertility. 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. The high mortality of the early embryo seems to be a general feature of ART but its causes and effectors are incompletely defined. It has been established that this high mortality is largely due to a marked retardation in ....Assisted reproductive technologies (ART, such as IVF and related techniques) are successful treatments for most forms of infertility. 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. The high mortality of the early embryo seems to be a general feature of ART but its causes and effectors are incompletely defined. It has been established that this high mortality is largely due to a marked retardation in the rate of cell cycle progression by embryo cells, and commonly is associated with a form of cell 'suicide', known as apoptosis. In non-embryonic cells a group of genes known as the tumour suppressor genes (TSGs) are responsible for slowing cell-cycle progression and are commonly involved in inducing apoptosis following cell stress. The role of TSGs in the early embryo is not well studied. We have recently shown that the most important of the TSGs, P53, is normally kept at very low levels in the early embryo but that ART causes up-regulation of its expression. This upregulation is a major cause of the embryopathy associated with ART in an animal model but that genetic mutations that prevent P53 expression favours increased embryo development and viability. This project will examine whether ART also causes up-regulation other important TSGs and whether this occurs in human embryos. We will examine the hypothesis that ART increases the survival of embryos with mutations to the P53 gene (creating a postive genetic selection pressure in favour of these mutations); and which aspects of ART cause this positive selection. The project will demonstarte whether changes in the ART procedures have the potential to mitigate against selection of embryos bearing deletrious mutations.Read moreRead less
Functional Genomic Analysis Of The Role Of P53 In Early Embryo Death After Assisted Reproductive Technologies (ART).
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
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 ....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.Read moreRead less