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
Understanding The Impact Of Preterm Birth On Development: Improving Outcomes For Preterm Infants.
Funder
National Health and Medical Research Council
Funding Amount
$823,008.00
Summary
Approximately 10% of babies are born prematurely and many suffer long-term health problems. Our aim is to understand how premature birth affects the development of the cardiovascular, respiratory and central nervous systems. This understanding will help to improve the long-term health outcomes for premature infants. By working with medical practitioners treating premature babies we are well placed to translate our findings on preventing and treating developmental injury into clinical practice.
Potential For Creatine Or Melatonin As Dietary Supplements In Pregnancy To Prevent Perinatal Brain Damage
Funder
National Health and Medical Research Council
Funding Amount
$483,217.00
Summary
Brain damage in the newborn - particularly in prematurely born infants - remains a significant health problem. At present there are very few treatments that can be used to minimize damage when it becomes apparent in the newborn, and none that can be used PROSPECTIVELYduring pregnancy to protect the developing brain from damage. The most likely cause of damage to the fetal brain during pregnancy or at birth is global ASPHYXIA, either by itself or in association with other problems of pregnancy su ....Brain damage in the newborn - particularly in prematurely born infants - remains a significant health problem. At present there are very few treatments that can be used to minimize damage when it becomes apparent in the newborn, and none that can be used PROSPECTIVELYduring pregnancy to protect the developing brain from damage. The most likely cause of damage to the fetal brain during pregnancy or at birth is global ASPHYXIA, either by itself or in association with other problems of pregnancy such as infection, preterm birth, or fetal growth retardation. In this project we propose that providing extra amounts of the dietary constituent creatine, or of the hormone melatonin, to the pregnant animal in late gestation, will provide NEUROPROTECTION to the developing brain in the face of an asphyxial challenge that otherwise causes damage. We will use pregnant sheep to investigate the effects of asphyxia in utero on the fetal brain using techniques that allow us to monitor metabolic changes within the brain in real time. In addition, we will use the pregnant Spiny Mouse to investigate the effects of birth asphyxia on the postnatal brain structure and behavioral development. We will study groups of animals fed a normal diet, and compare then to animals that receive additional amounts of creatine or melatonin. We expect to determine if either of these treatments have the potential to protect the developing brain from asphyxial damage, and to recommend if similar treatments could be used in pregnant women where the obstetrician suspects the baby's brain is at risk of damage.Read moreRead less
Does Caffeine Affect The Development Of The Very Immature Brain: Dose Response Relationship?
Funder
National Health and Medical Research Council
Funding Amount
$668,386.00
Summary
Premature birth is a major health problem worldwide. Preterm babies often develop apnoea of prematurity (AOP), which is commonly treated with caffeine. Trials indicate that preterm babies treated with low dose caffeine have less neurodevelopmental disabilities at 18 months. Higher doses of caffeine are often needed to reduce AOP but the risk of this is unknown. We will study the short and long-term effects of increasing doses of caffeine on the developing brain in a long-gestation species.
DEVELOPMENT OF FOLDING IN THE FETAL CEREBRAL CORTEX – IDENTIFYING FUNDAMENTAL MECHANISMS AND THEIR SUSCEPTIBILITY TO DISRUPTION IN NORMAL AND ABNORMAL PREGNANCY
Funder
National Health and Medical Research Council
Funding Amount
$607,742.00
Summary
During pregnancy, the surface of the fetal brain gradually develops the ridges, valleys, and folds that are the characteristic feature of our highly developed brain. However, this process can be disturbed if birth occurs prematurely, the unborn baby suffers oxygen starvation in the uterus, or the mother consumes alcohol. In this project we are determining how cell migration results in the development of brain surface folding, and how hypoxia and maternal alcohol consumption affect these importan ....During pregnancy, the surface of the fetal brain gradually develops the ridges, valleys, and folds that are the characteristic feature of our highly developed brain. However, this process can be disturbed if birth occurs prematurely, the unborn baby suffers oxygen starvation in the uterus, or the mother consumes alcohol. In this project we are determining how cell migration results in the development of brain surface folding, and how hypoxia and maternal alcohol consumption affect these important processes.Read moreRead less
Development Of The Commissural Plate And Its Role In Forebrain Commissure Development
Funder
National Health and Medical Research Council
Funding Amount
$529,565.00
Summary
During development, neurons in one hemisphere of the brain connect and communicate with neurons in the opposite hemisphere. Such neural connections between the two hemispheres are called commissures, which are large bundles of axons (neural-wires) that cross the midline of the brain. There are three commissures in the forebrain: the corpus callosum, the hippocampal commissure and the anterior commissure. This wiring of the brain is essential to its proper function. When these connections don't f ....During development, neurons in one hemisphere of the brain connect and communicate with neurons in the opposite hemisphere. Such neural connections between the two hemispheres are called commissures, which are large bundles of axons (neural-wires) that cross the midline of the brain. There are three commissures in the forebrain: the corpus callosum, the hippocampal commissure and the anterior commissure. This wiring of the brain is essential to its proper function. When these connections don't form, the brain cannot integrate and process information in fundamental ways. Over 50 different human congenital disorders are associated with the malformation of one or more of these forebrain commissures. This proposal investigates the hypothesis that a midline structure, called the commissural plate (CP), regulates the development of all forebrain commissures. The CP was first described anatomically at the turn of the 20th century in a number of different species, and in humans in 1968. However, since this time, no papers have been published on the CP. Experiments in this proposal will use modern neuroanatomical techniques, particularly magnetic resonance imaging, molecular and mouse mutagenesis techniques, and axon guidance assays, to study the CP. We will test the hypothesis that there is something fundamentally unique about the CP as the midline crossing point for all commissural axons. We generate mouse mutants that disrupt only dorsal CP formation and then determine whether the subsequent development of the dorsal commissures occurs. We also perform molecular expression, and imaging analyses on human foetal brains. Our goal is to provide an understanding of what developmental events are disrupted in human congential disorders resulting in midline brain malformations and agenesis of the forebrain commissures. Understanding the basis of these disorders will lead to more accurate diagnoses and potentially their prevention through genetic counseling.Read moreRead less
Carbon Dioxide As A Treatment For Seizures In The Newborn
Funder
National Health and Medical Research Council
Funding Amount
$878,389.00
Summary
This study aims to introduce a simple and effective treatment to prevent brain damage from seizures in babies using CO2. Neonatal seizures remain a major clinical problem worldwide and are associated with poor brain outcomes and significant risk of death. Recent trials in human adult epileptics show rapid and effective seizure suppression following the use of CO2. This therapy will significantly impact long-term outcomes for affected babies and reduce the burden of care for families and society.
Contribution Of Disturbed Blood Flow And Cerebral Metabolism To White Matter Damage In The Perinatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$369,375.00
Summary
It has been known for some time that the white matter regions of the developing brain are particularly vulnerable to damage. These regions are deep in the brain near the ventricles, and are rich in myelin sheaths wrapped around the nerve fibres running from cell-rich areas in the outer layers of the brain to other regions, and down into the spinal cord. Damage to white matter usually leads to behavioural, learning and motor problems in the newborn infant - in its severest form, seen as cerebral ....It has been known for some time that the white matter regions of the developing brain are particularly vulnerable to damage. These regions are deep in the brain near the ventricles, and are rich in myelin sheaths wrapped around the nerve fibres running from cell-rich areas in the outer layers of the brain to other regions, and down into the spinal cord. Damage to white matter usually leads to behavioural, learning and motor problems in the newborn infant - in its severest form, seen as cerebral palsy. Such outcomes are often associated with the presence of asphyxia and infection during pregnancy, leading to the belief that the damage first arises while the baby is still in utero. In this application we suggest that asphyxia and-or infection during pregnancy cause prolonged disturbances in the regulation of blood flow and integrity of the blood-brain barrier in the developing brain, together with changes in metabolism that result in accumulation of prostaglandins and the toxic hydroxyl radical, leading irreversibly to cell death. If this series of events proves to be true, we have suggested and will test several protocols for protecting the fetal brain, which should be readily translatable to clinical practice.Read moreRead less
Creatine, A Multi-organ Protectant Against Hypoxic Injury In The Neonate
Funder
National Health and Medical Research Council
Funding Amount
$524,802.00
Summary
The WHO estimates that up to 9 million babies suffer birth hypoxia each year, leading to 29% of global neonatal deaths, and significant rates of severe disability. We hypothesise that creatine, given as a supplement to the mothers diet during pregnancy, will protect her babies organs should low oxygen around the time of birth occur. The low cost of creatine is particularly relevant for rural and remote communities and the developing world where, currently, there are no effective therapies.
Understanding And Preventing Adverse Developmental Effects Of Perinatal Infection/inflammation
Funder
National Health and Medical Research Council
Funding Amount
$621,458.00
Summary
Exposure of babies to infection or inflammation within the womb is common and is associated with preterm delivery and illness in newborns. The biggest problem for these babies is lung disease due to inflammation of the lungs before birth and/or in response to lung injury after birth. We are investigating how inflammation alters lung development, and working on developing a novel cell therapy to prevent life-threatening newborn lung disease.