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.
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.
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.
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
Disorders of sexual development are among the most common form of birth defects in humans (1 in 4,000 births) because failure of the gonads to develop does not affect the viability of the individual. Such disorders can have profound psychological and medical consequences upon the individual, family, and society. Some intersexual conditions are the result of inappropriate exposure to hormones during fetal life, and others are due to spontaneous or inherited gene mutation. About 5-10% of ovarian c ....Disorders of sexual development are among the most common form of birth defects in humans (1 in 4,000 births) because failure of the gonads to develop does not affect the viability of the individual. Such disorders can have profound psychological and medical consequences upon the individual, family, and society. Some intersexual conditions are the result of inappropriate exposure to hormones during fetal life, and others are due to spontaneous or inherited gene mutation. About 5-10% of ovarian cancer cases, that affect 1 in 8000 Australian women, are due to the inheritance of a faulty gene. An understanding of the way gene expression and hence tissue differentiation is altered after sex reversal will inform us about the causes and consequences of normal and abnormal sexual development, gonadal malignancies and infertility. The gonad is unusual in that two completely different organs can arise from an essentially identical primordium, so that errors in development lead to intersexual phenotypes. We will use our new experimental animal model to clarify these processes.Read moreRead less
Effects Of Leptin On Follicle Growth And Ovulation
Funder
National Health and Medical Research Council
Funding Amount
$196,470.00
Summary
Leptin is a recently discovered hormone which is very important in controlling body weight. Extremely obese, or extremely underweight women, find it difficult to become pregnant, and leptin is probably the connection between weight and fertility. This may be a particularly important factor in polycystic ovary syndrome (PCOS), a distressing condition which affects 5% of women and causes both obesity and infertility. Exciting new research suggests that leptin also affects the immune system, and pr ....Leptin is a recently discovered hormone which is very important in controlling body weight. Extremely obese, or extremely underweight women, find it difficult to become pregnant, and leptin is probably the connection between weight and fertility. This may be a particularly important factor in polycystic ovary syndrome (PCOS), a distressing condition which affects 5% of women and causes both obesity and infertility. Exciting new research suggests that leptin also affects the immune system, and previous NH and MRC funding has enabled us to demonstrate that the immune system plays a crucial role in maintaining normal ovarian function. The nutritional status of the body, the immune system and the reproductive system all interact, and leptin appears to be the connecting link between these three major systems. We propose that leptin plays a major role in the ovary, and wish to determine how leptin mediates the effects of bodyweight and the immune system on ovarian function. Laboratory rats will be treated with leptin, their food intake and weight recorded, and a few weeks later the rats will have their ovaries removed. We will find out whether ovaries respond to leptin, or whether the ovarian response changes according to the menstrual cycle: perhaps leptin is very important just before ovulation, but it does not affect menstruation? Do any ovarian cells make leptin? Will leptin stimulate ovaries to produce more oestrogen or progesterone, or ovulate more eggs? We will also identify immune system cells in the ovary, and note whether leptin affects them. We will be able to relate all this data to weight and diet. Increased understanding of leptins' effect on the ovary has the potential to lead to new, improved treatments for PCOS or for unexplained cases of infertility. It is also possible that in the future a weight-loss regime might be developed which takes a womans monthly cycle into account, therefore making weight-loss more efficient and attainable.Read moreRead less
Building child health through maternal wellbeing. Chronic diseases partly originate in the health & social circumstances of previous generations, during pregnancy, and in conditions during infancy and childhood. This project will draw from three community studies the researcher established to investigate how aspects of women's health affect their children's health and identify new opportunities for disease prevention.
Roles Of TGFbeta Receptor TGFBR3 (Betaglycan) In Testis Development
Funder
National Health and Medical Research Council
Funding Amount
$332,660.00
Summary
Diseases of the reproductive tract are major health issues. At lease 1 in 100 live births display some sort of gonadal defects. Later in adulthood, one in six couples are affected by infertility, and cancers of the reproductive tract which result in a significant number of deaths each year. This project focuses on understanding the role of the transformation growth factor beta receptor3 (Tgfbr3) in the embryonic and neonatal testis and its impact on adult male reproductive capacities and health.