Functional Contribution Of Fetal Microchimeric Cells In Transgenic Models Of Maternal Tissue Repair In And After Pregnancy
Funder
National Health and Medical Research Council
Funding Amount
$542,462.00
Summary
Fetal stem cells cross into the mother during pregnancy and persist lifelong in her tissues. To determine whether helpful or harmful, we will study how these cells contribute to healing both after acute injury and in chronic genetic models like brittle-bone disease and muscular dystrophy. This research will inform long-term consequences of pregnancy, important for women's health and longevity, and help develop a promising form of stem cell therapy.
Impact Of Chronic Intrauterine Inflammation On Neurodevelopmental & Physiological Responses To Fetal Hypoxia.
Funder
National Health and Medical Research Council
Funding Amount
$280,750.00
Summary
Careful examination of records from hundreds of pregnancies has indicated that low-grade infection or inflammation within the uterus during pregnancy is associated with an increase in the likelihood that the newborn baby will suffer from cerebral palsy. This strong association suggests that inflammation during pregnancy can cause damage to the developing baby's brain. Similar studies have also identified an association betwen events that result in a lack of oxygen supply to the developing brain ....Careful examination of records from hundreds of pregnancies has indicated that low-grade infection or inflammation within the uterus during pregnancy is associated with an increase in the likelihood that the newborn baby will suffer from cerebral palsy. This strong association suggests that inflammation during pregnancy can cause damage to the developing baby's brain. Similar studies have also identified an association betwen events that result in a lack of oxygen supply to the developing brain and cerebral palsy. However the studies that have identified these associations are incapable of determining the mechanisms by which these factors affect brain development. Even though inflammation during pregnancy is common, and is often associated with diseases after birth, experimental studies of the effects of this type of inflammation on the wellbeing of the unborn baby have not been performed. Our research group has developed a unique experimental model, using sheep, which is particularly suitable for determining how inflammation and a lack of oxygen may affect the unborn baby and cause brain damage. By continuously giving a sterile bacterial cell wall preparation (endotoxin) into the amniotic fluid of pregnant sheep we can cause prolonged inflammation with characteristics that are similar to those that accompany inflammation during human pregnancy but different to other models of inflammation within the uterus. We intend to use our model to determine how prolonged inflammation and a lack of oxygen affect the well-being of the developing lamb before birth and how these factors affect brain development. Our proposed study will provide valuable information about how inflammation and a lack of oxygen interact to affect brain development. We expect that when inflammation is present the fetus becomes more vulnerable to the effects of a lack of oxygen, resulting in more severe brain damage occuring than when either factor is experienced alone.Read moreRead less
FETAL BRAIN INJURY RESULTING FROM INTRAUTERINE INFECTION: LONG TERM CONSEQUENCES AND THE POTENTIAL FOR INTERVENTION
Funder
National Health and Medical Research Council
Funding Amount
$452,640.00
Summary
Brain damage during fetal life is a significant cause of later neurological problems such as cerebral palsy. Recent studies have shown that brain injury detected in infants is usually caused by adverse conditions within the uterus prior to labour, but the exact causes are poorly understood. It is also apparent that babies born prematurely are at increased risk of suffering serious brain damage. Unfortunately, at present, it is not possible to prevent or effectively treat brain damage in the fetu ....Brain damage during fetal life is a significant cause of later neurological problems such as cerebral palsy. Recent studies have shown that brain injury detected in infants is usually caused by adverse conditions within the uterus prior to labour, but the exact causes are poorly understood. It is also apparent that babies born prematurely are at increased risk of suffering serious brain damage. Unfortunately, at present, it is not possible to prevent or effectively treat brain damage in the fetus or newborn, partly due to ignorance about how and when the damage is occurring. In recent years it has become evident that infections in the mother, may be linked to both premature birth and brain damage. It has been proposed that the certain chemicals (cytokines) which are released during an infection can across the placenta to the fetus, causing inflammatory changes that lead to brain damage. However, although associations have been shown in studies of women, there is little evidence that infections actually cause brain damage in the fetus. This project will define the effects of an inflammation inducing chemical (bacterial endotoxin) on the fetal brain and the pattern of inflammation it sets up in the fetus. We will also examine the effects of brain damage caused by endotoxin in the newborn lamb, and relate this to alterations in behaviour. Once we have defined the effects of endotoxin on brain structure, we will test the effects of chemicals that are known to block the actions of inflammatory cytokines. We hope that by blocking the chemical pathway that leads to the production of harmful cytokines we may be able to prevent brain injury from occurring when the fetus is exposed to an infection in the mother. It is expected that this project will provide important information that helps us to understand how infection in the mother can cause brain injury in the fetus. This information is vital if strategies to prevent or treat brain injury are to be developed.Read moreRead less
Prenatal Alcohol Exposure: A Molecular Mechanism For Memory Deficits Involving The Zinc-binding Protein, Metallothionein
Funder
National Health and Medical Research Council
Funding Amount
$277,645.00
Summary
Damage to the developing brain is the major social and economic consequence of prenatal alcohol exposure but it is unclear the mechanism by which this occurs. This study will assess whether the maternal zinc-binding protein, metallothionein, causes: 1) alcohol-related cognitive deficits, 2) changes in the expression of alcohol-sensitive cognitive genes. We will further assess whether dietary zinc supplementation throughout pregnancy can prevent alcohol-related anomalies in neurodevelopment.
Epigenetic Programming Of The Hypothalmo-Pituitary-Adrenal Axis
Funder
National Health and Medical Research Council
Funding Amount
$550,951.00
Summary
It has been shown that the pattern of nutrition in early pregnancy is important in determining the subsequent health of the fetus and newborn. Interestingly, the nutritional environment of the early embryo, when nutrient demands are minimal has been shown to be important in determining the development of the capacity of the fetus to respond to stress in the womb and the timing of delivery. This proposal seeks to understand the mechanisms that underlie these responses.
Insulin-like Growth Factor (IGF) -II, Cytotrophoblast Migration And Placental Development
Funder
National Health and Medical Research Council
Funding Amount
$487,750.00
Summary
During pregnancy, placental cells invade into the uterus and tap into the maternal blood vessels to procure an adequate blood supply for the growth of the placenta and hence the fetus. If this invasion process is impaired early in pregnancy, then the woman may suffer a miscarriage, if the process is impaired in mid-pregnancy then the mother may develop preeclampsia in which her blood pressure goes up and, in severe cases, placing her life and that of her unborn baby at risk. Miscarriage occurs i ....During pregnancy, placental cells invade into the uterus and tap into the maternal blood vessels to procure an adequate blood supply for the growth of the placenta and hence the fetus. If this invasion process is impaired early in pregnancy, then the woman may suffer a miscarriage, if the process is impaired in mid-pregnancy then the mother may develop preeclampsia in which her blood pressure goes up and, in severe cases, placing her life and that of her unborn baby at risk. Miscarriage occurs in 10-15% of pregnancies and preecclampsia in 7% of pregnancies. Preecclampsia may be life-threatening in up to 3% of all pregnancies and is a major cause of maternal death in pregnant women in Western countries. This project will examine the effect of treatment of the pregnant guinea pig with insulin-like growth factor-II on placental cell invasion and the capacity of the placenta to deliver nutrients to the fetus. We will also determine whether the effects of this treatment are mediated by a specific membrane receptor on the cell surface of the invading placental cells. We predict that this growth factor will enhance placental cell invasion and improve placental function. If this is the case then our findings may be developed for use in women at risk, to improve placental function and hence maternal and fetal health.Read moreRead less
Diagnostic Tests To Predict Risk For Life Threatening Pregnancy Complications
Funder
National Health and Medical Research Council
Funding Amount
$682,824.00
Summary
The main complications of pregnancy, preeclampsia, preterm birth and intrauterine growth restriction afflict 19% of first pregnancies and are life threatening to the mother or baby in 6% of pregnancies. Currently we have no way of knowing which women will suffer these diseases until symptoms manifest. We aim to develop genetic tests that can predict which women are at risk. This will permit earlier interventions that will improve the health of pregnant women and their babies.
Adults who were small at birth have a higher risk of coronary heart disease and adult onset diabetes. From a public health point of view the most important issue is to identify which factors in pregnancy cause low birthweight and lead to increased risk of adult disease. Growth of a fetus depends on the supply of oxygen and nutrients and the availability of nutrients will depend on both the mother's dietary intake and the transfer of nutrients, via the placenta, to the baby It is important that w ....Adults who were small at birth have a higher risk of coronary heart disease and adult onset diabetes. From a public health point of view the most important issue is to identify which factors in pregnancy cause low birthweight and lead to increased risk of adult disease. Growth of a fetus depends on the supply of oxygen and nutrients and the availability of nutrients will depend on both the mother's dietary intake and the transfer of nutrients, via the placenta, to the baby It is important that we understand the role of maternal nutrition in fetal growth because it is potentially modifiable. Although we know that birthweight falls in times of famine little is known about whether the composition of a mother's diet in a developed society affects birthweight and later health of the offspring. We plan to study this in twin pregnancies, since maternal nutrition is more stretched and any effects should be magnified and more readily identified. It may be that maternal nutrition only matters if the placenta is not working as well as it should. Unfortunately there is no good measure of how well the placenta is working, but we will measure erythropoietin level in infants as a marker of whether they were getting enough oxygen via the placenta, and see whether there is any evidence that maternal nutrition matters more as the infant shows more signs of poor oxygen supply. In twins we can look between pairs for evidence that maternal nutritional factors affect birthweight, at twins within pairs to see whether oxygen supply or other individual factors are important and we can compare all infants as individuals to see how these different factors interact. We plan to study 200 women with twin pregnancies in Melbourne and Adelaide. Once we have identified factors influencing birthweight, we will be in a position to plan future studies to determine which are associated with increased risk markers for cardiovascular diseaseRead moreRead less
The Fetal Response To Infection, With Particular Reference To Alterations Of Tryptophan Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$410,616.00
Summary
Infection in pregnancy has long been known to be associated with a high risk for brain damage in the baby. There is now good evidence that the brain can be damaged before birth, and in other babies where the brain is damaged after birth there is reason to say that these infants were factors associated with the pregnancy that rendered them vulnerable to risk factors postnatally. Very little is known about the effects of infection on the fetus. Some recent work has shown that substances released f ....Infection in pregnancy has long been known to be associated with a high risk for brain damage in the baby. There is now good evidence that the brain can be damaged before birth, and in other babies where the brain is damaged after birth there is reason to say that these infants were factors associated with the pregnancy that rendered them vulnerable to risk factors postnatally. Very little is known about the effects of infection on the fetus. Some recent work has shown that substances released from bacteria induce cells in the uterus and placenta to produce inflammatory chemicals that can damage the brain. In this project we propose the following model: 1), infection causes the release of substances from the uterus and placenta that disrupt the blood-brain barrier in the fetal brain; and, 2), infection alters the metabolism of the essential amino acid tryptophan in the fetus, causing greater production of metabolites that have toxic effects on the developing brain. We have preliminary evidence to support these two proposals. If the idea is proven correct, it should be possible to administer simple analogues of tryptophan to prevent the toxic metabolites of this amino acid from increasing in the fetus when either the mother or the uterus becomes infected. Because these substances can be given by mouth, this would allow a simple treatment to be developed for women at risk of infection, or who are already infected. This would be particularly useful wherever medical services and resources are limited, as for under-priviledged groups and in Third World countries.Read moreRead less