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
Neuroactive Steroids In The Fetal Brain: Role In The Regulation Of Behaviour And Protection Against Hypoxia
Funder
National Health and Medical Research Council
Funding Amount
$65,685.00
Summary
The major breakdown products of the steroid hormone, progesterone, form a group of hormones termed neuroactive steroids. These steroids have major effects on the activity of the brain and influence behaviour in adult subjects. Changes in the production of steroids by the steroid producing glands influences neurosteroid levels in the adult brain. This in tern may cause behavioural and mood changes in adults, leading to conditions such as premenstrual stress and postnatal depression. In fetal life ....The major breakdown products of the steroid hormone, progesterone, form a group of hormones termed neuroactive steroids. These steroids have major effects on the activity of the brain and influence behaviour in adult subjects. Changes in the production of steroids by the steroid producing glands influences neurosteroid levels in the adult brain. This in tern may cause behavioural and mood changes in adults, leading to conditions such as premenstrual stress and postnatal depression. In fetal life, the placenta releases large amounts of these neuroactive steroids and high concentrations of these steroid are found in the fetal circulation. We have shown that these steroids suppress the activity of the fetal brain, suppress arousal and maintain the fetus in a sleep-like state during pregnancy. In this proposal we investigate the hypothesis that cells in the fetal brain modify the neuroactive steroid environment within the brain so as to suppress fetal brain activity further during times of stress and, therefore, protect the brain from damage caused by excessive excitation. These mechanisms may prevent brain injury due to placental insufficiency during pregnancy and asphyxia during birth. The augmentation of these natural processes may form the bases for treatment strategies to provide additional protection for the fetal brain in high-risk pregnancies.Read moreRead less
Essential Protective Role Of Neuroactive Steroids In The Fetal And Neonatal Brain.
Funder
National Health and Medical Research Council
Funding Amount
$422,036.00
Summary
Brain injury may occur during complicated pregnancies and at birth, as well as in neonates following preterm labour, and is a major problem in neonatal medicine. The consequent nerve cell death leads to ongoing neurological impairment which represents a major cost to the individual and to the community. Neuroactive steroids are hormones related to the steroid hormone progesterone that have been shown to have a major influence on nerve cell activity and nervous transmission. While these hormones ....Brain injury may occur during complicated pregnancies and at birth, as well as in neonates following preterm labour, and is a major problem in neonatal medicine. The consequent nerve cell death leads to ongoing neurological impairment which represents a major cost to the individual and to the community. Neuroactive steroids are hormones related to the steroid hormone progesterone that have been shown to have a major influence on nerve cell activity and nervous transmission. While these hormones influence mood and behaviour in adult subjects, they have an even more important role in the fetus which is exposed to high levels of steroids from the placenta. The fetus is very sensitive to these neuroactive steroids and we have shown that they suppress the activity of the fetal brain so as to maintain the fetus in a sleep-like state during pregnancy. Periods of low oxygen supply (hypoxia) to the fetus may occur during pregnancy, as well as result from asphyxia at birth, and may lead to excessive excitation of nerve cells resulting in nerve cell death. Steroid-induced suppression reduces excitation of nerve cells and results in the fetus being resistant to excessive excitation. In this proposal we investigate the hypothesis that cells in the fetal brain modify the neuroactive steroid environment within the brain so as to suppress fetal brain activity further during times of hypoxic stress and, therefore, further protect the brain from damage caused by excessive excitation. These mechanisms may prevent brain injury due to placental insufficiency during pregnancy, asphyxia during birth and in premature babies. We will investigate whether the supplementation of these processes by administering neuroactive steroids may provide additional nerve protection during high-risk periods during pregnancy. These studies may identify a new as yet unexploited group of natural compounds which may improve infant health without adverse actions on the mother or baby.Read moreRead less
Improving Outcomes For Premature Infants Through Effective Maintenance Of Systemic Blood Flow
Funder
National Health and Medical Research Council
Funding Amount
$789,383.00
Summary
Survival rates for preterm babies are increasing, but the rate of disability is still high. Preterm babies may experience inadequate blood flow to the brain, leading to longterm disability. The causes of low blood flow are not known and current treatments are ineffective in nearly half of cases. This study will confirm that low blood flow is the result of immaturity of the structure and-or control of the heart, and will test new treatments targeted to these systems in the baby.
The Role Of Platelet Derived Growth Factor Receptor Alpha (Pdgfra) In Coronary Vascular Progenitor Cells
Funder
National Health and Medical Research Council
Funding Amount
$666,840.00
Summary
The coronary vessels supply blood to heart muscle. Blockage of coronary vessels causes heart attacks which are the leading cause of death in the Western world. A recent focus for heart attack researchers is to re-establish the blood supply to the injured area by creating new blood vessels. We have found a new gene involved in creating coronary blood vessels. We will characterize how this gene is involved in this process. Knowledge about this gene may foster new treatments for heart attack.
The Association Of Cerebral Palsy With Fetal Thrombophilia, Infection And Inherited Susceptibility To Infection.
Funder
National Health and Medical Research Council
Funding Amount
$123,500.00
Summary
Cerebral palsy (CP) is a group of permanent and non-progressive disorders of movement and posture that manifest early in life, resulting from damage to the immature brain. It is the most common major physical disability in childhood, affecting approximately 2 in every 1000 children born in Australia. Until recently, it was assumed that CP was a result of foetal asphyxia during birth. However, recent studies suggest that asphyxia around the time of birth accounts for less than 6% of all CP cases. ....Cerebral palsy (CP) is a group of permanent and non-progressive disorders of movement and posture that manifest early in life, resulting from damage to the immature brain. It is the most common major physical disability in childhood, affecting approximately 2 in every 1000 children born in Australia. Until recently, it was assumed that CP was a result of foetal asphyxia during birth. However, recent studies suggest that asphyxia around the time of birth accounts for less than 6% of all CP cases. In the remaining cases the neuropathology becomes established during pregnancy. Recent evidence suggests that maternal infection (bacterial and possibly viral), and also inherited fetal clotting disorders are often implicated in the development of CP. It is now possible to test stored dried blood spots from babies who subsequently developed CP. Using the modern technology of gene probes for inherited clotting disorders, markers of susceptibility to infection and bacterial or viral infection during pregnancy, some of the antenatal causes of CP may be identified. The identification of the causes of CP may lead to its prevention.Read moreRead less
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
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
Cerebrovascular Effects Of Intrauterine Hypoxia: Contribution To Perinatal Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$579,138.00
Summary
During pregnancy, delivery of oxygen and nutrients to the growing fetus is sometimes disturbed, and can lead to injury of the developing brain. In this project we investigate the idea that low oxygen (hypoxia) causes brain demage to blood vessels in the fetal brain, and new blood vessesl produced in an attempt to repair this damage are fragile and prone to rupture, explaining the high incidence of bleeding in the brain of prematurely-born and full term infants that experience birth hypoxia.