Macrophage-regulated Tissue Remodelling In Endometrial Receptivity For Embryo Implantation And Pregnancy Success
Funder
National Health and Medical Research Council
Funding Amount
$456,779.00
Summary
Infertility and recurrent miscarriage affect 60-80 million couples globally, including 15% of couples in Australia. Moreover, 1 in 6 pregnancies is affected by pre-eclampsia, low birth weight or preterm labour. Infertility and other pathologies in pregnancy often result from failure of the maternal tissues to adequately support embryo implantation and development of the placenta, leading to insufficient nutritional support of the developing fetus. We have discovered in mice that disruption in th ....Infertility and recurrent miscarriage affect 60-80 million couples globally, including 15% of couples in Australia. Moreover, 1 in 6 pregnancies is affected by pre-eclampsia, low birth weight or preterm labour. Infertility and other pathologies in pregnancy often result from failure of the maternal tissues to adequately support embryo implantation and development of the placenta, leading to insufficient nutritional support of the developing fetus. We have discovered in mice that disruption in the populations of immune cells called macrophages within the uterine endometrial lining can reduce the receptivity of the endometrum to embryo implantation, and can lead to fetal growth retardation and impaired health after birth. The purpose of this project is to delineate the precise functions of macrophages in interacting with other cells in the endometrium to facilitate attachment of the embryo, its invasion into maternal tissues, and its access to an adequate blood supply as the placenta develops during early pregnancy. We will employ state of the art experimental strategies including genetic models to deplete endometrial macrophage populations in mice, and will then study the implications for changes in endometrial tissue structure and function. Furthermore we will investigate the long term consequences of early macrophage perturbations for the fetus and neonate after birth. This study will improve our understanding of how determinants of macrophage function such as infection and inflammatory conditions, male factors, nutrition and stress can impair fertility and compromise optimal pregnancy outcome in humans.Read moreRead less
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE120100082
Funder
Australian Research Council
Funding Amount
$180,000.00
Summary
FACSAria III - Fluorescence activated cell sorter. Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. The FACSAria III cell sorter will be used to establish a core facility for sorting cells. The outcomes from using this technology are a better understanding cellular and genetic understanding of cancer, respiratory diseases, reproduction and ....FACSAria III - Fluorescence activated cell sorter. Flow cytometry is a technique for counting and examining microscopic particles, such as cells and chromosomes, by suspending them in a stream of fluid and passing them by an electronic detection apparatus. The FACSAria III cell sorter will be used to establish a core facility for sorting cells. The outcomes from using this technology are a better understanding cellular and genetic understanding of cancer, respiratory diseases, reproduction and birth. Read moreRead less
The role of a novel protein, interferon epsilon, in reproductive tract immunity. This project aims to develop a world-first description of a new protein that has a protective role against female reproductive tract infections. This unique protein, called interferon epsilon, was discovered in our laboratory. This project will facilitate development of new therapeutic approaches of benefit in diseases such as Chlamydia and Herpes Simplex Virus.
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
Understanding Immune Tolerance In Pregnancy To Discover A New Intervention For The Treatment Of Pre-eclampsia
Funder
National Health and Medical Research Council
Funding Amount
$492,202.00
Summary
Pre-eclampsia is a common complication of pregnancy. Women who develop pre-eclampsia experience high blood pressure, swelling and lose protein in the urine. There is no treatment for pre-eclampsia other than delivery of the baby. Pre-eclampsia has risks for the mother and the baby. This research will discover whether generalised inflammation in the mother is a cause of pre-eclampsia and will evaluate the role of a novel treatment for its potential to prevent this life threatening condition.
This research deals with the interaction between the reproductive system and the immune system, providing a unique perspective on two biological systems that are normally considered separately. This research may help to improve the treatment of infertility, reproductive tract infections and testicular cancer, but may also lead to new treatments for inflammatory diseases that hospitalise or kill many thousands of patients each year, and for preventing graft failure in transplant recipients.
This study aims to determine the extent to which semen is important in initiating the maternal immune response to the fetus and placenta during pregnancy. We postulate that exposure to paternal proteins in sperm and other factors present in the semen may have a cumulative, beneficial effect in 'educating' the female immune system to respond in the correct way to the embryo when pregnancy occurs. To investigate this, the behaviour and movements of white blood cells responding to semen will be stu ....This study aims to determine the extent to which semen is important in initiating the maternal immune response to the fetus and placenta during pregnancy. We postulate that exposure to paternal proteins in sperm and other factors present in the semen may have a cumulative, beneficial effect in 'educating' the female immune system to respond in the correct way to the embryo when pregnancy occurs. To investigate this, the behaviour and movements of white blood cells responding to semen will be studied during the period after mating, in which the uterus prepares for and accommodates to pregnancy. In particular, the study will focus on the roles of a specific chemical messenger substance in semen, called transforming growth factor (TGF)-beta, which triggers the molecular changes leading to maternal immune tolerance. A deeper understanding of these events will have an important impact in human and veterinary medicine where implantation failure is a major cause of reproductive loss and inadequate placental growth poses a threat to the health of the conceptus both in utero and into adult life.Read moreRead less
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.
The Male Partner Contribution To Pregnancy Immune Tolerance Deficit In Women
Funder
National Health and Medical Research Council
Funding Amount
$1,462,925.00
Summary
A complication-free pregnancy and birth of a healthy infant depends on adequate preparation of the mother's immune system to tolerate the 'foreign' fetus, Both the mother and the father contribute to establishing optimal immune tolerance. This project will determine the links between specific agents in male seminal fluid and the female immune response, and will make progress towards new diagnostic tests and treatment options for unexplained subfertility and gestational disorders.