Astrocyte Regulation Of Ammonia And Glutamate In Neonatal Hypoxia-Ischaemia
Funder
National Health and Medical Research Council
Funding Amount
$523,804.00
Summary
Lack of oxygen is a common problem for newborn infants, ocurring during events such as a difficult labour, and can lead to brain damage. We have discovered that a protein in the brain which normally removes ammonia (a toxic product of metabolism) is rapidly lost after a brief period of low oxygen. We propose that a build up of ammonia in the brain may be a key damaging event in hypoxia-related brain injury, and that it will be ameniable to therapeutic intervention.
Neonatal Vitamin D Status And Risk Of Schizophrenia: A Study Using Danish Dried Bloods Spots
Funder
National Health and Medical Research Council
Funding Amount
$164,980.00
Summary
There is increasing evidence that low levels of vitamin D (i.e. the 'sunshine hormone') during early development can alter brain development. In particular, it has been proposed that low vitamin D during development (e.g. prenatal and in early life), increases the risk of developing schizophrenia during adulthood. A previous study based on stored third trimester blood samples from US women suggested that very low levels of maternal vitamin D may be associated with an increased risk of schizophre ....There is increasing evidence that low levels of vitamin D (i.e. the 'sunshine hormone') during early development can alter brain development. In particular, it has been proposed that low vitamin D during development (e.g. prenatal and in early life), increases the risk of developing schizophrenia during adulthood. A previous study based on stored third trimester blood samples from US women suggested that very low levels of maternal vitamin D may be associated with an increased risk of schizophrenia in the offspring. We have the opportunity to explore this hypothesis using a large, well-described Danish 'bio-bank'. Since 1981, blood samples from newborn babies have been kept by a central agency in Denmark. In collaboration with senior Danish medical researchers, 900 blood samples of babies who have subsequently developed schizophrenia and 1800 from matched healthy individuals have been identified. We will measure vitamin D levels in these blood samples. We predict that babies with low levels of vitamin D will have an increased risk of developing schizophrenia. If low prenatal vitamin D does increase the risk of schizophrenia, this finding will have important implications from a public health perspective. Just as the number of infants affected by spina bifida has been reduced by adding folate supplements to foods, optimizing maternal vitamin D levels may lead to a reduction in the incidence of schizophrenia.Read moreRead less
INVESTIGATING THE VALIDITY OF PRENATAL INSULTS AS RISK FACTORS FOR SCHIZOPHRENIA.
Funder
National Health and Medical Research Council
Funding Amount
$201,100.00
Summary
Schizophrenia is one of the most devastating of human mental disorders affecting about 1% of the population. The cause of this disorder is not known but it seems certain that it will involve genetic and environmental factors. An adverse environmental factor could be a reduced supply of oxygen and nutrients to a baby during pregnancy. In guinea pigs we aim to investigate whether disruption to the normal supply of oxygen and nutrients to the fetus disrupts the normal fine structure and chemical ma ....Schizophrenia is one of the most devastating of human mental disorders affecting about 1% of the population. The cause of this disorder is not known but it seems certain that it will involve genetic and environmental factors. An adverse environmental factor could be a reduced supply of oxygen and nutrients to a baby during pregnancy. In guinea pigs we aim to investigate whether disruption to the normal supply of oxygen and nutrients to the fetus disrupts the normal fine structure and chemical make up of the brain and gives rise to long-lasting structural and neurochemical changes in adolescent animals, which resemble changes found in the brains of patients with schizophrenia. We will also assess whether behavioural responses of compromised animals are altered in tests that parallel disturbances seen in patients with schizophrenia. Such abnormal brain development could create an underlying vulnerability in the brain, predisposing individuals with risk factors such as genetic inheritance to develop the symptoms of schizophrenia in later life perhaps only after the complete formation of nerve pathways involved in higher brain functioning. If guinea pigs that have been subjected to low oxygen levels during pregnancy show sustained changes in the structure and neurochemistry in regions of the brain that are altered in patients with schizophrenia it would suggest that these long lasting disturbances could result from problems during pregnancy. Thus, this would support the idea that abnormal brain development during pregnancy is one of the underlying causes of schizophrenia.Read moreRead less
Defining The Genetic And Environmental Factors That Cause Abnormal Vertebral Segmentation During Embryogenesis
Funder
National Health and Medical Research Council
Funding Amount
$724,147.00
Summary
Many birth defects cause vertebral malformations along the spinal column. They originate as the fetus forms, and may be caused by gene mutation or environmental factors. Whilst studying one type of vertebral malformation we have found a genetic cause for 30% of cases. We will investigate the genetic and environmental cause of the remainder. We will look for new genes causing this disease, and use a mouse model to learn how low oxygen levels during pregnancy causes such malformations
PROTECTING THE PRETERM FETAL BRAIN FROM HYPOXIA AND INFECTION: A HEALTHY START TO LIFE.
Funder
National Health and Medical Research Council
Funding Amount
$495,750.00
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. In recent years it has become evident that infections in the mother may be linked to both premature bi ....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. 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 certain chemicals (cytokines), which are released during an infection, can cross the placenta to the fetus causing inflammatory changes that lead to brain damage. We have shown that an inflammatory inducing chemical (bacterial endotoxin) administered to immature fetal sheep induces brain damage similar to that seen in cerebral palsy. This provides an excellent model for testing agents that are known to block the action of cytokines and other markers of inflammation; currently there is no effective strategy for the treatment or prevention of hypoxia and inflammatory induced injury of the brain partly due to our ignorance about how and when the damage is occurring. We will test the effects of two chemicals; N-acetyl cysteine, which is known to block the generation of inflammatory cytokines, and the naturally occurring glycoprotein erythropoietin, which prevents death of neurons (apoptosis). We hope that by blocking these pathways we may be able to prevent brain injury from occurring when the immature fetus is exposed to an infection during gestation. We expect that this project will provide important novel information that helps us to understand how infection in the mother can cause brain injury in the fetus and provide a new approach for strategies to prevent or treat brain injury.Read moreRead less
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
Measuring Hypoxia Induced MRNA In Maternal Blood To Monitor Wellbeing Of Growth-restricted Fetuses
Funder
National Health and Medical Research Council
Funding Amount
$421,358.00
Summary
Severely growth restricted fetuses are at peril of stillbirth from low oxygenation. While ultrasound monitoring improves outcomes, babies are still lost. Better ways to monitor the health the unborn baby are needed. We have recently discovered fetuses’ starved of oxygen leak RNA into mother's blood. Thus, measuring RNA molecules in blood could be used to assess fetal health. We will examine whether measuring mRNA in maternal blood could be used to monitor wellbeing of growth-restricted fetuses.
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.
The Impact Of Severe Asthma During Pregnancy On Placental Function And Fetal Hypothalamic-pituitary-adrenal Function
Funder
National Health and Medical Research Council
Funding Amount
$209,242.00
Summary
This study will examine whether the glucocorticoids administered for the control of severe asthma during pregnancy affects placental and fetal function. It is known that severe asthma during pregnancy is associated with low birth weight babies but the events that cause reduced growth of the baby are unknown. However in both animal and human pregnancies, increased exposure of the baby to glucocorticoids from the mother causes growth restriction of the baby. Therefore we propose that the increased ....This study will examine whether the glucocorticoids administered for the control of severe asthma during pregnancy affects placental and fetal function. It is known that severe asthma during pregnancy is associated with low birth weight babies but the events that cause reduced growth of the baby are unknown. However in both animal and human pregnancies, increased exposure of the baby to glucocorticoids from the mother causes growth restriction of the baby. Therefore we propose that the increased intake of glucocorticoids for the treatment of asthma during pregnancy changes how the placenta functions and allows the fetus to be exposed to maternal glucocorticoids causing changes in fetal development. We will examine placental blood flow and measure some placental enzymes that may be involved in the control of blood flow in placentas collected from women with mild, moderate and severe asthma and compare them to non-asthmatic women. We will look at placental blood flow in utero using Doppler ultrasound and also in vitro after the placenta is delivered. We want to see if the fetus is affected by increased intake of glucocorticoids by the mother by measuring a hormone estriol, which originates from the fetus. We will measure estriol throughout pregnancy as it can easily be detected in the mothers' urine. These studies will tell us if glucocorticoid intake for the treatment of asthma can exert effects on the placenta and baby during pregnancy. These studies will make a significant contribution both scientifically and clinically. At a scientific level we will be able to examine how increased maternal glucocorticoid intake during pregnancy affects placental mechanisms and whether these changes affect the fetus and clinically the outcome of this study will allow us to optimize asthma therapy during pregnancy so that we can improve the outcome for the baby.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