Oxygen, Oxidative Phosphorylation And Regulation Of Embryo Development.
Funder
National Health and Medical Research Council
Funding Amount
$141,096.00
Summary
There is concern that human infertility treatment requiring the growth of embryos in the laboratory, as applied in human IVF, may cause problems during fetal development or even possibly lead to health problems much later in life as an adult. In particular, many clinics are now growing human embryos outside the body for several days longer (to select the best embryos for transfer) than what occurred a decade ago. This concern is based on the evidence that the environment in which an embryo grows ....There is concern that human infertility treatment requiring the growth of embryos in the laboratory, as applied in human IVF, may cause problems during fetal development or even possibly lead to health problems much later in life as an adult. In particular, many clinics are now growing human embryos outside the body for several days longer (to select the best embryos for transfer) than what occurred a decade ago. This concern is based on the evidence that the environment in which an embryo grows in has an impact on the way in which some genes are switched on and off. Normal on-off switching at appropriate times during early development should lead to healthy offspring. Failure to turn off or on, or inappropriate timing, may lead to consequences that manifest themselves later in development. We believe that oxygen concentration and the activity of mitochondria, the organelles of cells that converts oxygen into energy, are key regulators in turning on and off genes during early embryo development. This is because we have shown that, in embryos of a species that is metabolically similar to the human embryo, oxygen concentration and mitochondria activity need to change as the embryo grows for optimal development in the laboratory. In other mammalian cells, oxygen and mitochondria activity are known to turn on or off several particular genes, known as transcription factors. Transcription factors are genes which regulate other genes. Therefore, transcription factors are good candidates as regulators of early embryo development. The present project aims to determine if factors such as changing oxygen concentration and mitochondria activity during laboratory growth of embryos affects the way in which these transcription factors turn on and off. If we find this is true, the way in which human embryos are grown in the laboratory needs to be examined carefully to minimize the risk of possible long-term consequences to the resulting fetus.Read moreRead less
Positional Candidate Targets For Multiple Ovulation Genes
Funder
National Health and Medical Research Council
Funding Amount
$272,036.00
Summary
The frequency of non-identical twins is associated with fertility in individuals and populations, although we know little about mechanisms for twinning or effects on fertility. The likelihood for giving birth to non-identical twins is influenced by genetic factors. The probability of a subsequent twin pregnancy is increased fourfold in mothers of twins and roughly doubled for women whose mother or sister has had non-identical twins. Understanding why some women are more likely to have twins will ....The frequency of non-identical twins is associated with fertility in individuals and populations, although we know little about mechanisms for twinning or effects on fertility. The likelihood for giving birth to non-identical twins is influenced by genetic factors. The probability of a subsequent twin pregnancy is increased fourfold in mothers of twins and roughly doubled for women whose mother or sister has had non-identical twins. Understanding why some women are more likely to have twins will help us find key pathways that control normal ovarian function and important factors that influence success in assisted reproduction. The aim of this project is to search for these genes in families with two sisters who have given birth to non-identical twins. Previous studies have identified one strong target region and two possible regions containing genes for increased twinning. We now have additional families and will examine each region in more detail. We will also look for genes within each region that could be responsible for variation in twin frequency.Read moreRead less
Understanding The Determinants Of Human Oocyte And Embryo Health
Funder
National Health and Medical Research Council
Funding Amount
$252,761.00
Summary
This project will address key questions involving how the human egg and embryo maintain their ability to develop into a healthy fetus. In recent years there have been significant advances in our understanding of how animal oocytes grow and become competent as well as an increased understanding of how the animal embryo maintains its viability in culture. Currently there is little information as to how the human oocyte and embryo develops. This study will address the current lack of knowledge by e ....This project will address key questions involving how the human egg and embryo maintain their ability to develop into a healthy fetus. In recent years there have been significant advances in our understanding of how animal oocytes grow and become competent as well as an increased understanding of how the animal embryo maintains its viability in culture. Currently there is little information as to how the human oocyte and embryo develops. This study will address the current lack of knowledge by extending the information gathered in animal models to establish how the human oocyte communicates with its surrounding cells and how this communication is important for development. We will also study how the developing embryo maintains its physiology and metabolism and the relationship between the ability to control metabolic balance and viability will be established. All of the questions outlined in this proposal can be performed without disturbing the oocyte and developing embryo by analysing the surrounding cells and the spent media. Therefore, all of these questions can be answered non-invasively. The outcome of this proposal will be an increased understanding of how the physiology and development of the human oocyte and embryo is maintained. However, importantly this data will then provide information as to the relationship of these parameters to developmental competence. Therefore, it will be possible to establish a range of markers that can be used to predict the developmental competence of a human embryo. Currently multiple embryos are routinely transferred in an IVF cycle resulting in an increase in multiple gestation pregnancies and their associated complications. The information generated in this study will provide information enabling markers to be used to identify the most viable embryo from a cohort, which is essential if single embryo transfer is to be universally adopted in an IVF program.Read moreRead less
Comparison Of Pregnancy Outcomes Following Transferring One Or Two Embryos In A Selected Group Of Infertility Patients.
Funder
National Health and Medical Research Council
Funding Amount
$120,302.00
Summary
Assisted reproductive technology (ART) deals with issues of fundamental importance to individuals involved, and society as a whole. Despite major advances, ART continues to be very costly in many regards. A major reason for this is the relatively low rate of pregnancy, which averages 25% per procedure. The common response to the problem of low pregnancy rates is to return several embryos to uterus. A dilemma associated with this strategy is the high risk of multiple pregnancy, which is associate ....Assisted reproductive technology (ART) deals with issues of fundamental importance to individuals involved, and society as a whole. Despite major advances, ART continues to be very costly in many regards. A major reason for this is the relatively low rate of pregnancy, which averages 25% per procedure. The common response to the problem of low pregnancy rates is to return several embryos to uterus. A dilemma associated with this strategy is the high risk of multiple pregnancy, which is associated with adverse consequences for mother and fetus(es). Compared to singleton births; fetal, neonatal, and perinatal mortality rates are 3-6 times higher in twins, and 5-15 times higher in multiple births of a higher order. Cerebral palsy rates among survivors are six times higher in twins and twenty times higher in triplets. The increase in the incidence of adverse outcomes related to multiple pregnancy has been well documented in ART. We propose a randomised controlled study to assess single embryo transfer (SET) compared to double embryo transfer (DET). Infertility women with a high risk of multiple pregnancy will be randomly allocated to receive one or two embryos, which is the usual treatment at present. We shall then examine the rates of single and multiple pregnancies, and the success of those pregnancies in this group of patients. Potential benefits to the community from this project are very substantial, as it has the capacity to substantially reduce the number of multiple births. Patients will also benefit by having more accurate information with which to make an informed choice during treatment.Read moreRead less
Identification Of Factors Essential For Oocyte Viability
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
Approximately 2% Australia children are now conceived using in vitro fertilisation technologies, allowing infertile couples to bear their own children. However, a major consequence of IVF techniques is multiple pregnancies (i.e. twins and triplets) which is a major health risk to mothers and their infants. Furthemore, IVF increases birth defects, which are mostly attributed to the increased multiple pregnancies, but is also observed in pregnancies involving a single infant. It is essential that ....Approximately 2% Australia children are now conceived using in vitro fertilisation technologies, allowing infertile couples to bear their own children. However, a major consequence of IVF techniques is multiple pregnancies (i.e. twins and triplets) which is a major health risk to mothers and their infants. Furthemore, IVF increases birth defects, which are mostly attributed to the increased multiple pregnancies, but is also observed in pregnancies involving a single infant. It is essential that IVF techniques are developed that enables the transfer of a single embryo to the mother resulting in the birth of a single healthy baby, without the ethical concerns of surplus embryo disposal. Women receiving IVF are required to adminster hormones that stimulate the eggs in their ovaries to mature to the point where they can be fertilised by their partner's sperm. These hormones, called gonadotrophins, override the body's own ovarian stimulating system and cause many eggs to mature and be collected for fertilisation, instead of normally just one. In this way, the best embryo(s) can be selected for transfer back to the mother, and other embryos can be frozen and stored for later use. However, large doses of gonadotrophins has consequences. They can be dangerous to some patients who are sensitive to their potency, and stimulate a massive response. They also reduce the quality of eggs and subsequent embryos, which reduces the chances of a pregnancy. All this can be avoided if eggs can be collected from ovaries in an immature state and maturation achieved in the laboratory. However, although attempted, this has not been a successful technique, primarily because we don't understand the process of human egg maturation. Our research will investigate the biochemistry, physiology and genetics of non-human eggs and embryos resulting from eggs that are grown and matured in the laboratory, to develop techniques for the successful maturation of human eggs in the laboratory.Read moreRead less
Metabolic And Molecular Determinants Of Embryo Viability
Funder
National Health and Medical Research Council
Funding Amount
$551,321.00
Summary
We know that our health as adults is influenced by the lifestyle of our mothers during pregnancy. In particular, increased risk of adult-onset diseases such as diabetes and cardiovascular disease occurs when small and lean infants at birth are raised in conditions where nutrient intake is not restricted and obesity occurs. This concept of fetal programming is now widely accepted. Our laboratory is leading research in a new concept, that of embryonic programming. We have extensive animal data dem ....We know that our health as adults is influenced by the lifestyle of our mothers during pregnancy. In particular, increased risk of adult-onset diseases such as diabetes and cardiovascular disease occurs when small and lean infants at birth are raised in conditions where nutrient intake is not restricted and obesity occurs. This concept of fetal programming is now widely accepted. Our laboratory is leading research in a new concept, that of embryonic programming. We have extensive animal data demonstrating that exposure of embryos to physiological perturbations alters fetal development, similarly to that occurring in nutrient restriction during pregnancy. Furthermore, there is data from IVF-derived children that their birth-weight is lower than expected, possibly due to the conditions used for conception in the laboratory. How does the response by eggs and embryos, at the time of conception, affect subsequent development? There has been some focus on changes to DNA that are not related to mutations, but structural changes in the DNA that alters gene expression. We call this epigenetics and epigenetic changes are found in embryos, including human embryos following IVF. However, no one knows how such epigenetic changes occur as a result of this stress response by the egg or embryo. Our proposal is to determine the mechanism of how epigenetic alterations take place in eggs and embryos. Our theory is that the mitochondria, the energy producing packages within all cells, are sending signals to the embryo's nucleus. When the egg or embryo finds itself in adverse conditions, the signals change as a result of changes in the energy balance. This in turn changes the activity of enzymes in the nucleus that regulates DNA structure. If we can prove that this relationship occurs, then we can assess these changes in human embryos that are excess to a patient's requirements and learn if programming takes place in human embryos.Read moreRead less