The Role Of Placental Transcription Factors In The Pathogenesis Of Fetal Growth Restriction
Funder
National Health and Medical Research Council
Funding Amount
$601,582.00
Summary
We must understand the role of growth control genes in the growth of the human placenta. The reason is that in several significant placental disorders, placental formation is abnormal and prevents the placenta from functioning efficiently. This in turn, impacts on the growth of the developning fetus. A variety of established and innovative methods described in this project will determine the functions of the placental growth control genes and may lead to novel therapeutic targets.
I am a reproductive biologist - reproductive immunologist investigating the role of the female immune response and its cellular and molecular agents in establishing pregnancy. My research spans basic science and clinical and commercial transfer, and aims to improve our understanding of the factors determining optimal reproductive health in women leading to better treatments for infertility and pathologies of pregnancy, and the best possible health outcomes for babies and children.
Prevention Of Placental Oxidative Stress And Inflammation By Dietary Omega-3 Fatty Acids
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Several pregnancy disorders that result in low birthweight involve aberrant function of the placenta. In this project we will examine one of the key mechanisms underlying placental dysfunction, namely oxidative stress, and determine whether its adverse effects can be limited by supplementation with dietary omega 3 fatty acids. The outcomes of this project will help guide future clinical studies on the possible beneficial effects of omega-3 fatty acids in pregnancy.
P-glycoprotein: A New Player In The Placental Glucocorticoid Barrier
Funder
National Health and Medical Research Council
Funding Amount
$424,711.00
Summary
Adequate growth and development of the fetus are crucial for survival of the newborn. The placenta plays a central role in these processes, providing the fetus with appropriate nutrients and hormonal signals. The placenta also regulates the maternal-fetal passage of hormones, some of which have the capacity to limit fetal growth. These include glucocorticoid hormones from the mother's adrenal gland (eg cortisol) which are normally prevented from passing through the placenta to the fetus due to t ....Adequate growth and development of the fetus are crucial for survival of the newborn. The placenta plays a central role in these processes, providing the fetus with appropriate nutrients and hormonal signals. The placenta also regulates the maternal-fetal passage of hormones, some of which have the capacity to limit fetal growth. These include glucocorticoid hormones from the mother's adrenal gland (eg cortisol) which are normally prevented from passing through the placenta to the fetus due to the 'placental glucocorticoid barrier'. The primary focus of this proposal is the investigation of a potential new contributor to this barrier called P-glycoprotein (P-gp), recently shown to limit access of glucocorticoids to the brain. We propose that because the placenta expresses significant amounts of P-gp, it may help prevent maternal glucocorticoids from reaching the fetus and causing growth retardation. We will determine whether P-gp is a significant contributor to the placental glucocorticoid barrier, and measure how much P-gp is present in normal placentas throughout pregnancy. We will also assess whether there is less P-gp present in placentas of growth-retarded fetuses. Understanding how P-gp affects the passage of glucocorticoids across the placenta could help to treat certain cases of fetal growth retardation.Read moreRead less
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
GM-CSF Regulation Of Preimplantation Embryo Development
Funder
National Health and Medical Research Council
Funding Amount
$481,320.00
Summary
Treatment of infertility using IVF technology has been enormously successful. However, there are major concerns regarding the high incidence of multiple pregnancies (caused by the transfer of more than one embryo) and the potential adverse health outcome of adults conceived from this technology. Multiple pregnancies place both mother and infant at enormous risks, with increased obstetrics care, prematurity, increased neonatal care and neurological disorders such as cerebral palsy. This can be ov ....Treatment of infertility using IVF technology has been enormously successful. However, there are major concerns regarding the high incidence of multiple pregnancies (caused by the transfer of more than one embryo) and the potential adverse health outcome of adults conceived from this technology. Multiple pregnancies place both mother and infant at enormous risks, with increased obstetrics care, prematurity, increased neonatal care and neurological disorders such as cerebral palsy. This can be overcome simply by the transfer of a single embryo. However, patient and clinical expectations are that single embryo transfer should be achieved with little to no reduction in pregnancy rate, and currently this is not possible because our methods for culturing embryos are inadequate. Studies in animals suggest that laboratory growth of mammalian embryos can lead to small-for-gestational age babies (even when the effect of multiple births is taken into consideration). This backed by recent studies which agree that babies born from IVF are smaller than expected. This might lead to health problems in later life, as smallness at birth is associated with higher risks of cardiovascular disease and diabetes, especially as age progresses beyond 40 years. However, the oldest IVF child is currently 23 years of age. Previously we have shown that a protein growth factor, called granulocyte-macrophage colony-stimulating factor (GM-CSF), found normally in the reproductive tract, has dramatic beneficial effects on human and mouse embryos grown in the laboratory. Furthermore, we have shown in mice that embryo exposure to GM-CSF alleviates the detrimental side effects of in vitro culture on foetal growth and body structure after birth. Our research is now focussed on understanding why this protein is beneficial to embryo growth and to test if we can increase pregnancy rates and produce normal healthy infants from the transfer of single embryos treated with GM-CSF.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
Development Of Engineered Novel Growth Factors For Infertility Treatment
Funder
National Health and Medical Research Council
Funding Amount
$410,439.00
Summary
Infertility comes at an enormous social and financial cost to Australian society. The aim of this proposal is to improve the success rate of an innovative technology that matures eggs in the laboratory and so eliminates the need for the hormones normally used in IVF. To achieve this a newly discovered egg-secreted protein first has to be produced in the laboratory.