The Role Of IGF2 And MTOR In Placental Development In Normal And Pregnancy Perturbations
Funder
National Health and Medical Research Council
Funding Amount
$207,002.00
Summary
20% of Australian women develop a problem during pregnancy which can cause illness or death of mother or baby. These are linked with poor placental growth and function. This project will identify novel regulators of human and mouse placental development using state-of-the-art molecular and cellular techniques. This will provide a better understanding of placental development and potentially direct future diagnostic and therapeutic strategies for pregnancy complications
Interleukin 11 And Leukemia Inhibitory Factor: Pivotal Regulators Of Uterine Receptivity And Placental Function
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
Infertility, spontaneous abortion and pre-eclampsia are major clinical problems. Interleukin (IL)-11 and leukemia inhibitory factor (LIF) are critical for embryo implantation in mice but their mechanisms of action in women are not well defined. We will define their roles in the establishment of pregnancy and provide new critical information on their potential as targets for diagnostic and therapeutic tools for infertility and major diseases associated with pregnancy.
Interstitially Invasive Trophoblast Of The Murine Placenta: Developmental Origins, Functions And Gene Expression.
Funder
National Health and Medical Research Council
Funding Amount
$369,717.00
Summary
Due to the obvious limitations to studying human pregnancy, the mouse has become a valuable model. However, invasion of the placenta into the uterine wall and vasculature, critical for successful pregnancy, is poorly understood in the mouse. The aims of the proposal are designed to gain a better understanding of these processes in mice and will provide a more accurate model system to study serious pregnancy complications resulting from abnormal placental invasion, such as preeclampsia.
Why Is Trophoblast Invasion Defective In Human Pregnancies That Develop Pre-eclampsia
Funder
National Health and Medical Research Council
Funding Amount
$504,500.00
Summary
Pre-eclampsia is the most common serious medical disorder of otherwise healthy young pregnant women. Early in pregnancies destined for pre-eclampsia, placental cells (cytotrophoblasts) do not invade deeply enough into maternal blood vessels within the uterus, with resultant low oxygen levels and reduced blood flow from the mother's circulation to placenta. This causes fetal under-nutrition and growth restriction, which if severe, can cause intrauterine death. To prevent this, the baby may need t ....Pre-eclampsia is the most common serious medical disorder of otherwise healthy young pregnant women. Early in pregnancies destined for pre-eclampsia, placental cells (cytotrophoblasts) do not invade deeply enough into maternal blood vessels within the uterus, with resultant low oxygen levels and reduced blood flow from the mother's circulation to placenta. This causes fetal under-nutrition and growth restriction, which if severe, can cause intrauterine death. To prevent this, the baby may need to be delivered prematurely, with grave risks of complications, both short and longterm. Women with pre-elampsia suffer from hypertension, activation of the clotting system, and generalized constriction of blood vessels. Together, these result in damage to blood vessel lining cells, reduced blood flow to, and disturbed function of many organs. Most commonly affected are kidney, liver, brain, and the uterine circulation. Babies born early and-or small-for-gestational-age have an increased incidence of vascular disease, hypertension, diabetes and kidney disease in adult life. Improved understanding, and development of preventive and-or therapeutic strategies for pre-eclampsia are urgently needed. There is no satisfactory animal model to address pathogenesis of this peculiarly human disorder, which concurrently causes significant morbidity in two generations of people. Ethical constraints and the need for urgent therapy limit extensive research in affected pregnant women. With our unique in vitro cell co-culture strategy, we have clarified inter-relationships between fetal-placental cells (cytotrophoblasts) and their host maternal vascular cells (decidual endothelial cells) in the clinical syndrome of pre-eclampsia. Building on this work we will now examine maternal-placental intercellular cooperation in regulation of normal placental development, and explore the defective regulation of placental development that precedes pre-eclampsia.Read moreRead less
Glucose, Glucose Transporters And Blastocyst Formation In The Mouse
Funder
National Health and Medical Research Council
Funding Amount
$281,650.00
Summary
Embryo-based biotechnologies have the potential to improve human reproductive health, notably in treating infertility by In vitro fertilisation (IVF). They are also central to the future use of embryonic stem cells for human tissue replacement. This project investigates the molecular mechanisms controlling one of the earliest differentiations in the growth of the embryo. Using the mouse as an experimental model it will investigate the importance of several factors in the changes which set up the ....Embryo-based biotechnologies have the potential to improve human reproductive health, notably in treating infertility by In vitro fertilisation (IVF). They are also central to the future use of embryonic stem cells for human tissue replacement. This project investigates the molecular mechanisms controlling one of the earliest differentiations in the growth of the embryo. Using the mouse as an experimental model it will investigate the importance of several factors in the changes which set up the placenta and fetus as seperate tissues in the very early embryo. A key focus is the supply of glucose to the newly fertilised embryo and how important this glucose supply is for the survival of the embryo. Moreover there is great interest in the possibility that metabolic events in utero can contribute to the development of diseases in later life, notably, coronary heart diease, stroke, high blood pressure and non-insulin dependent diabetes. The results from these studies will contribute to our understanding of why some couples are infertile, lead to improved management of infertility by diet and invitro fertilisation procedures. It will also be of benefit in dietary advice to women with diabetes mellitus, seeking to have children. The adenoviral strategy for gene delivery into early mouse embryos may in the long term also find wide clinical application in the treatment of genetic defects at the very earliest stages in development and as such is of enormous potential benefit in the management of both animal and human reproduction.Read moreRead less
Immunobiology Of Early Pregnancy - A Model Of Virus-induced Abortion
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
Summary
The lack of 'self' molecule expression on the trophoblast cells of the placenta which interface directly with the mother's circulation, as well as the local suppression of the mother's immune response at this interface, may be important factors in the successful implantation of the embryo. This immunological 'silence' allows the embryo, whose paternal genetic contribution makes it immunologically foreign to the mother, to escape the rejection reaction normally associated with foreign graft trans ....The lack of 'self' molecule expression on the trophoblast cells of the placenta which interface directly with the mother's circulation, as well as the local suppression of the mother's immune response at this interface, may be important factors in the successful implantation of the embryo. This immunological 'silence' allows the embryo, whose paternal genetic contribution makes it immunologically foreign to the mother, to escape the rejection reaction normally associated with foreign graft transplantation. Infection with flaviviruses increases the concentrations of cell surface self and adhesion molecules in vertebrate cells, including the trophoblast cells of the placenta. As a result, these molecules can then be recognised by the maternal immune system and the embryo targeted for destruction. We hypothesise that the induction of these molecules by this and other viruses may break the immunological silence of the early embryo and reverse the local suppression of the maternal immune response. This would result in maternal immune rejection of the embryo and abortion. This initial sensitisation of the mother by the virus might be one of the reasons that some women suffer recurrent abortions. We will use a novel viral mouse model where we implant virus-infected embryos into receptive animals to enable us to dissect out the unusual requirements for induction of maternal anti-viral immunity during pregnancy. This model was developed in our laboratory to directly test our hypotheses. It does not cause systemic illness in the mother which itself can lead to non-specific abortion. This model therefore can for the first time elucidate the specific mechanisms associated with the delicate balance between eradicating virus and maintaining pregnancy. Results from this project will inform rational design of treatment of recurrent abortions in the community.Read moreRead less