Women are born with a limited supply of eggs and are unable to make new eggs after birth. Because of this, the number and health of eggs established within the ovary early in life influence the length of time for which a female will be fertile, her age at menopause, and the health of her offspring. This project aims to shed some light on the mechanisms that control egg supply and reproductive longevity in women by investigating the role of the cell death protein Bid within the ovary.
Female fertility and age at menopause are determined by the number and quality of eggs stored in the ovaries. For unknown reasons, two-thirds of all eggs die soon after they are made. Furthermore, a serious side effect of cancer treatment is egg death resulting in infertility and early menopause. I am unravelling the genes involved in determining whether an egg will live or die. This understanding will help us develop novel strategies to preserve fertility during aging and cancer treatment.
BH3-only Proteins Are Critical For The Developmentally Programmed Death Of Oocytes: Impact On Ooctye Quality And The Fertile Lifespan
Funder
National Health and Medical Research Council
Funding Amount
$273,537.00
Summary
The ability of women to have healthy children, and the age at which menopause occurs, are largely dependent on the number and quality of the eggs stored in their ovaries. For unknown reasons, around two-thirds of all eggs die very shortly after they are made. We are unraveling the genes involved in determining whether an egg will live or die, and are investigating the role of these genes as _quality control sentinels", responsible for ensuring that only the highest quality eggs are ovulated.
Genes to phenotype: Exploiting the marsupial model. This research will exploit one of Australia's finest natural resources, its marsupial fauna. The features of marsupial reproduction and development provide a unique opportunity to answer fundamental biological questions. This research will show how the minor differences in key developmental genes that have arisen in their 100 million year isolation give rise to the characteristic differences in developmental timing and reproduction between mar ....Genes to phenotype: Exploiting the marsupial model. This research will exploit one of Australia's finest natural resources, its marsupial fauna. The features of marsupial reproduction and development provide a unique opportunity to answer fundamental biological questions. This research will show how the minor differences in key developmental genes that have arisen in their 100 million year isolation give rise to the characteristic differences in developmental timing and reproduction between marsupials and other mammals. The focus on reproduction and development will also provide invaluable knowledge to underpin efforts to conserve our endangered species and to control those that are overabundant.Read moreRead less
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
Cellular signals controlling oocyte activation. This research will significantly advance our understanding of the basic biological processes that underpin the fertility rate of all mammals and are key to the immediate and future health and well-being of Australian landscape and society. Understanding the processes that maintain healthy quiescent oocytes over many years before activation and subsequent growth will enable development of methods of increasing productivity in domestic animals and en ....Cellular signals controlling oocyte activation. This research will significantly advance our understanding of the basic biological processes that underpin the fertility rate of all mammals and are key to the immediate and future health and well-being of Australian landscape and society. Understanding the processes that maintain healthy quiescent oocytes over many years before activation and subsequent growth will enable development of methods of increasing productivity in domestic animals and enhancing fertility in endangered species. Knowledge of these cellular mechanisms will underpin biotechnology platforms necessary for novel methods of feral animal population control thus contributing at multiple levels to an economically sustainable Australia.Read moreRead less
Extrinsic Control of Mammalian Germ Cell Delineation. Australia is a leader in the recent exciting breakthroughs in reproduction and development, such as cloning and embryonic stem cell propagation, and understanding how germ cells are specified would help us understand the biology underlying specification and developmental potential of all cells. This research will continue to contribute to maintaining Australia's high reputation in advances in reproductive biology. In addition, a greater under ....Extrinsic Control of Mammalian Germ Cell Delineation. Australia is a leader in the recent exciting breakthroughs in reproduction and development, such as cloning and embryonic stem cell propagation, and understanding how germ cells are specified would help us understand the biology underlying specification and developmental potential of all cells. This research will continue to contribute to maintaining Australia's high reputation in advances in reproductive biology. In addition, a greater understanding of marsupial reproduction is a high priority for Australia in the 21st century, with its current unacceptably high rate of mammalian extinctions, for 'we cannot conserve until we comprehend' (Short, 1985).The results therefore are of great potential benefit to society.
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Constructing an embryo. This project investigates the cellular and molecular mechanisms underlying temporal and spatial organisation in the eutherian preimplantation embryo. It will examine: the relative roles of cell cycle and circadian clocks in developmental timing; the molecular mechanism by which intercellular adhesion patterns influence spatial organisation; the extent to which marsupials use similar timing and spatial localisation mechanisms to eutherians; the impact of in-vitro manipulat ....Constructing an embryo. This project investigates the cellular and molecular mechanisms underlying temporal and spatial organisation in the eutherian preimplantation embryo. It will examine: the relative roles of cell cycle and circadian clocks in developmental timing; the molecular mechanism by which intercellular adhesion patterns influence spatial organisation; the extent to which marsupials use similar timing and spatial localisation mechanisms to eutherians; the impact of in-vitro manipulations over the first 5 days of mouse pregnancy on embryonic temporal and spatial organisation.Read moreRead less
Mechanistic basis of a reproductive lesion in transforming growth factor beta-1 (TGFb1) null mutant mice. Null mutation in the gene encoding the cytokine transforming growth factor beta-1 (TGFb1) causes infertility in male and female mice. In recent experiments we have found that TGFb1 deficiency is associated with impaired ovarian and testicular steroidogenesis, arrested development of pre-implantation embryos and disrupted mammary gland morphogenesis. The aims of the current project are to un ....Mechanistic basis of a reproductive lesion in transforming growth factor beta-1 (TGFb1) null mutant mice. Null mutation in the gene encoding the cytokine transforming growth factor beta-1 (TGFb1) causes infertility in male and female mice. In recent experiments we have found that TGFb1 deficiency is associated with impaired ovarian and testicular steroidogenesis, arrested development of pre-implantation embryos and disrupted mammary gland morphogenesis. The aims of the current project are to unravel the mechanistic basis of the reproductive lesion in TGFb1 null mutant mice and to determine the effect of exogenous systemic delivery of TGFb1 in alleviating this lesion. It is expected that the project will provide new insight into key roles for TGFb1 in governing male and female fertility, and shed light on the prospects for exogenous supplementation of TGFb1 for improving reproductive performance in wild-type animals. This knowledge has potentially important applications in the livestock breeding industry, in devising novel contraceptive vaccine strategies, in the human pharmaceutical industry, and in devising novel contraceptive vaccine strategies.Read moreRead less