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
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
Molecular Mechanisms Regulating Spontaneous Onset Of Human Labour
Funder
National Health and Medical Research Council
Funding Amount
$481,156.00
Summary
The single most important complication contributing to poor pregnancy and neonatal outcome is premature birth. If we are to provide the best possible start to life, improve perinatal health and reduce the risk of developing adult disease . A better understanding of labour is requisite to improving health care delivery during pregnancy and outcomes for both mother and baby. This reserach project will investigate the how labour-associated events are reguluated by nuclear proteins.
The Mechanisms That Regulate The Onset Of Human Labour And Delivery
Funder
National Health and Medical Research Council
Funding Amount
$528,170.00
Summary
Reproductive biologists still cannot explain the molecular mechanisms that govern human birth. This lack of knowledge prevents the development of better moitoring and treament of complications of labour and delivery. If we are to provide the best possible start to life and improve newborn health care delivery then we must: (1) better understand what triggers labour; (2) determine whether there are biomarkers that we can use to identify women at risk of early birth; and (3) identify new ways to d ....Reproductive biologists still cannot explain the molecular mechanisms that govern human birth. This lack of knowledge prevents the development of better moitoring and treament of complications of labour and delivery. If we are to provide the best possible start to life and improve newborn health care delivery then we must: (1) better understand what triggers labour; (2) determine whether there are biomarkers that we can use to identify women at risk of early birth; and (3) identify new ways to delay birth. This is the overall objective of this research project. In particular, this project focuses on how the multiple events needed to achieve a successful outcome to pregnancy are coordinated at the time of birth.Read moreRead less
Mechanisms Of Escape From Progesterone-induced Suppression: Role In Normal And Preterm Birth
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Prematurity caused by preterm birth is the leading cause of death and disease among newborns in Australia. Here we will define how the length of pregnancy is determined by the opposing actions of progesterone, which maintains pregnancy, and prostaglandins, which induce labour. We will demonstrate the mechanism by which the actions of the two hormones are balanced in normal pregnancy and disrupted in preterm labour. We will show that preterm birth can be prevented by correcting the disorder.
Determining The Impacts Of Epigenetic Modifying Drugs On Germline Programming And Offspring Health
Funder
National Health and Medical Research Council
Funding Amount
$863,918.00
Summary
New drugs have been developed that inhibit specific enzymes that regulate epigenetic pathways in cells. These pathways significantly affect growth and development in offspring and may represent a risk to future children of patients taking the drug. This project will determine these risks and provide data for developing clinical guidelines for safe use of the drugs.
Preterm birth is a major cause of neonatal death and cerebral palsy. This grant will provide proof-of-concept that a computer program can be developed to predict a pregnant woman�s risk of preterm birth. There is a large market (4M US and 8M Europe), there are no competing technologies. This is a unique collaboration between Biomedical Engineering and an Australian centre with an international reputation in preterm birth, assisted by a pathology company.
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
Risk Of Birth Defects In Children Born Following Infertility Treatment
Funder
National Health and Medical Research Council
Funding Amount
$191,962.00
Summary
The development of assisted reproductive technology (ART) for infertility treatment has advanced at a tremendous pace since late 1970's. The use of ART is becoming increasingly frequent, with Australia having one of the highest rates of use internationally. Over 4,000 births result from ART annually in Australia. At the same time, minimally invasive infertility treatment-ovulation induction and insemination, remains a main option for some infertile couples and also generates several thousand bir ....The development of assisted reproductive technology (ART) for infertility treatment has advanced at a tremendous pace since late 1970's. The use of ART is becoming increasingly frequent, with Australia having one of the highest rates of use internationally. Over 4,000 births result from ART annually in Australia. At the same time, minimally invasive infertility treatment-ovulation induction and insemination, remains a main option for some infertile couples and also generates several thousand births annually. A fundamental concern for those involved in infertility treatment is the health of the children born following the treatment. Evidence from many studies indicates that compared to the general population, ART babies are more likely to be a twin or triplet, have a low birth weight, be born premature, and suffer higher rates of perinatal death and cerebral palsy. These issues are gradually being addressed by transferring a single embryo in a cycle. Of greater concern is the recent reporting by a Western Australian team that the risk of major birth defects is doubled in ART children. This is a highly significant finding that has raised concern in patients and clinicians. It is imperative to verify the findings through replication in a larger study. It is equally important to identify whether the increased risk is due to potentially modifiable treatment factors or patient factors related to their infertility. This innovative study will therefore also separate patient characteristics and type of treatment, and partition the risk attributable to various factors. The health of children from infertility treatments is of fundamental concern and has become an important public health issue. This study will direct future basic research in embryology and clinical services where there is a continual need to balance technical innovation and efficacy with treatment safety. The long-term benefit will be improvement of the health status of Australian families.Read moreRead less