I am a developmental lung physiologist who specialises in understanding the factors regulating normal and abnormal lung development as well as the physiological transformation of the lung into an efficient gas-exchange organ at birth.
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
Physical Determinants Of Lung Development Before And After Birth
Funder
National Health and Medical Research Council
Funding Amount
$442,500.00
Summary
Survival at birth is critically dependent upon the ability of the lungs to take on the role of exchanging gases; a role previously performed by the placenta. The lungs must, therefore, have grown and matured sufficiently during fetal life, before they are required at the time of birth. Inadequate development of the lungs during fetal life is the most common cause of death and disease in newborn babies. This may be due to premature birth, when the lungs have had insufficient time to develop, or i ....Survival at birth is critically dependent upon the ability of the lungs to take on the role of exchanging gases; a role previously performed by the placenta. The lungs must, therefore, have grown and matured sufficiently during fetal life, before they are required at the time of birth. Inadequate development of the lungs during fetal life is the most common cause of death and disease in newborn babies. This may be due to premature birth, when the lungs have had insufficient time to develop, or it may be due to inappropriate lung development during fetal life. It is important therefore, to understand the mechanisms that control growth and development of the lung both before and after birth. During fetal life the lungs are filled with liquid which expands the lungs and provides a stretch stimulus causing them to grow. Previously we have shown that a reduction in the degree of fetal lung expansion causes lung growth to cease. Likewise, if we increase the degree of lung expansion in the fetus, we induce a rapid increase in fetal lung growth and maturation. This stimulus is so potent that it can reverse an existing lung growth deficit, thus enabling survival of the newborn. In this application we will investigate the mechanisms by which alterations in lung expansion induce growth and maturation of the lung. Specifically we will investigate the role of calmodulin in fetal lung growth, because the genes that encode it are activated when the lung cells are growing most rapidly. In addition, we will identify other genes that are turned on or off during rapid growth of the lung because those genes are likely to play important roles in the regulation of fetal lung growth and development. We will also investigate the underlying differences in the control of lung growth at different stages of gestation, as well as investigate factors that regulate lung growth after birth, particularly in prematurely born animals.Read moreRead less
Control Of Alveolar Epithelial Cell Differentiation Before And After Birth
Funder
National Health and Medical Research Council
Funding Amount
$376,980.00
Summary
In the lung, gas exchange takes place in small terminal airsacs called alveoli. The internal surface of the alveoli are lined with 2 types of specialist cells, the type-I and type-II cells, which are essential for the normal functioning of the lung. Although both cell types look completely different and have very different functions, they are derived from the same precursor cell. However, it is not known what determines whether these cells will become a type-I or a type-II cell. This application ....In the lung, gas exchange takes place in small terminal airsacs called alveoli. The internal surface of the alveoli are lined with 2 types of specialist cells, the type-I and type-II cells, which are essential for the normal functioning of the lung. Although both cell types look completely different and have very different functions, they are derived from the same precursor cell. However, it is not known what determines whether these cells will become a type-I or a type-II cell. This application is directed towards understanding the mechanisms which determine the fate of these cells. This is critical information as the lung must have the correct proportions of both cell types to function properly as a gas exchange organ.Read moreRead less
The survival of a baby at birth is crtically dependent upon the ability of the lungs to successfully take over the role of exchanging oxygen and carbon dioxide between the air and blood. To perform this task, during fetal life the lung must have grown properly and near the end of gestation it must mature both structurally and biochemically. Thus, babies that are born early, before the expected time of birth, are born before the lungs have had the opportunity to mature. It is not surprising, ther ....The survival of a baby at birth is crtically dependent upon the ability of the lungs to successfully take over the role of exchanging oxygen and carbon dioxide between the air and blood. To perform this task, during fetal life the lung must have grown properly and near the end of gestation it must mature both structurally and biochemically. Thus, babies that are born early, before the expected time of birth, are born before the lungs have had the opportunity to mature. It is not surprising, therefore, that an inability to breathe is one of the primary problems faced by a prematurely born infant. During late gestation the lung changes dramatically in order to increase its ability to exchange gases. There is an increase in surface area and a reduction in the barrier thickness between the airspace and the blood stream. The molecular mechanisms involved in this remodelling are unknown, but it is known that the administration of corticosteroids to women at risk of preterm labour causes a large decrease in this barrier thickness and increases the distensibility of the lung. This project seeks to understand how the structure of the lung matures in late gestation and to determine whether corticosteroids regulate these changes by altering the structure of a specialised molecule, called versican. Versican resides in the tissue space outside of cells and has special properties that allow it to retain water and help organise the surrounding matrix. We propose that alterations in the structure of versican will reduce its ability to retain water, thereby reducing the tissue volume and contributing to a reduction in the air-blood tissue barrier within the lung.Read moreRead less
Fetal Responses To Intra-uterine Inflammation And The Postnatal Pulmonary Consequences
Funder
National Health and Medical Research Council
Funding Amount
$347,036.00
Summary
There is increasing evidence that exposure of the unborn baby to infection and inflammation may be the cause of several important and disabling illnesses in later life, including long-term lung injury and brain damage. Hospital-based studies have shown that infants who go on to develop these diseases have signs of inflammation before, and soon after, birth. These studies in humans, however, have only shown associations between inflammation and later disease. Carefully controlled scientific exper ....There is increasing evidence that exposure of the unborn baby to infection and inflammation may be the cause of several important and disabling illnesses in later life, including long-term lung injury and brain damage. Hospital-based studies have shown that infants who go on to develop these diseases have signs of inflammation before, and soon after, birth. These studies in humans, however, have only shown associations between inflammation and later disease. Carefully controlled scientific experiments are required to show that inflammation actually causes damage and to allow us to find ways to prevent or cure the diseases that result from such injury. In 1998, using sheep, our research group discovered a way to produce inflammation in the fetus without endangering its wellbeing or causing early labour. The inflammation is caused by injecting a sterile bacterial cell wall preparation (endotoxin) into the amniotic fluid surrounding the fetus. Using this model, we have found that an episode of inflammation before birth profoundly increases lung maturity, thus increasing the chances of survival if premature birth occurs. Based on our information from humans, we expect that if these lambs are allowed to survive past the first few days after birth, they will go on to develop chronic lung disease, and perhaps brain damage. This study will answer vital questions about the events that occur in the uterus and the fetus during periods of inflammation, and will then determine the long-term consequences in the weeks following birth. We expect that these lambs will have changes which at first will increase their chances of survival after birth, to be followed by chronic disability due to lung and brain damage. If confirmed, this finding will allow us to find treatments which can be applied before birth to ensure that children are less likely to be born with these disabling illnesses.Read moreRead less
Preventing Prenatal Brain Injury In Fetal Growth Restriction
Funder
National Health and Medical Research Council
Funding Amount
$511,294.00
Summary
Intrauterine fetal growth restriction (IUGR) is a serious complication of pregnancy associated with increased perinatal morbidity and mortality. In particular, IUGR infants have a high risk of perinatal brain injury which is likely to arise from damage before birth. Our aim is to use an ovine model of IUGR to define the causes of that brain injury and to develop new therapies that could be offered to women to protect their unborn baby.
Neuroactive Steroids In The Developing Brain: Potential For Preventing Perinatal Brain Damage
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Complications during pregnancy, birth asphyxia or premature birth can lead to serious neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neuroactive steroids are a group of neuromodulators that are derived from the hormone progesterone. These steroids fall into two groups, those that appear to protect brain cells from damage caused by an inadequate supply of oxygen and those that may increase cell death. We have shown tha ....Complications during pregnancy, birth asphyxia or premature birth can lead to serious neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neuroactive steroids are a group of neuromodulators that are derived from the hormone progesterone. These steroids fall into two groups, those that appear to protect brain cells from damage caused by an inadequate supply of oxygen and those that may increase cell death. We have shown that protective neuroactive steroids are present in very large amounts in the fetal brain. Steroids produced by the placenta are converted to these neuroactive products by enzymes in the brain leading to the high levels that are seen during fetal life. Certain adverse conditions during pregnancy as well as preterm birth may cause marked changes in the balance of steroids that could increase susceptibility to brain injury. We have found that areas of the brain, where damage most often occurs, normally contain the highest amount of protective steroids, but only in late pregnancy. This suggests that disturbances that lower steroid production in these areas could contribute to the death of cells, particularly in mid-pregnancy and after premature birth. In the proposed studies, we will examine whether a toxic balance of steroids develops following adverse events in pregnancy as well as the areas of the brain where this is most pronounced. We will examine the changes in the expression of enzymes that can potentially cause the accumulation of protective steroids in the brain. We will then examine treatments that can raise the concentration of steroids and determine which combination of steroids best reduces cell death and brain injury following complications during pregnancy. The findings of this work will indicate the best therapeutic approach that may be adopted to modify the concentration of certain steroids so as to reduce the risk of brain damage in the fetus and neonate.Read 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