Neurosteroid Mediated Protection After Birth: Approaches For Maximising Protective Steroid Levels In The Neonatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$450,703.00
Summary
Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the ....Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the fetal brain and levels rise further in response to fetal stress. The placenta contributes steroid precursors that help maintain these high neurosteroid levels. This placenta-fetal brain interaction comprises an internal mechanism that protects the fetal brain from adverse events during pregnancy. At birth, however, there is a dramatic decline in neurosteroid concentrations in the brain after the loss of the placental precursor supply. The fall in concentrations is even greater in animals that are born growth restricted. This suggests that newborns, particularly those from compromised pregnancies, are at increased risk of brain damage due to low neurosteroid levels. We believe that certain commonly used steroid therapies may also lower steroid levels in the brain and result in increased vulnerability to brain damage during birth or in the early neonatal period. Alternatively, we propose that replacement of neurosteroid precursors in the newborn may raise brain neurosteroid levels and protect against brain damage. In the proposed studies we will evaluate treatments that can raise the concentration of steroids and determine the best strategy for reducing brain injury following complications during pregnancy, at birth and during the early newborn period. This work will determine the best therapeutic approaches for maximising neurosteroid-induced brain protection and for reducing the risk of brain damage.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.
Improving The Prediction And Detection Of Contributors To Term Stillbirth
Funder
National Health and Medical Research Council
Funding Amount
$570,358.00
Summary
Stillbirths are a global human tragedy, with 1 in 130 of all pregnancies in Australia ending in stillbirth. We propose to use ultrasound and blood markers to improve the detection of babies who are not growing well, a leading risk factor for stillbirth. Sleep position has also been associated with stillbirth, so we will study fetal heart rate responses during an overnight sleep study to see if breathing events overnight may be an important contributor to stillbirth in growth restricted fetuses.
Hypoxia-induced Suppression Of Respiratory Sensations And Reflexes
Funder
National Health and Medical Research Council
Funding Amount
$276,750.00
Summary
Many diseases that effect the respiratory system have their primary effect on the lungs and airway themselves but in some conditions, such as obstructive sleep apnea (OSA) and asthma, increased breathing load can induce periods of low blood oxygen which could further contribute to morbidity in these diseases. OSA is a disorder associated with snoring. Patients experience periods of sleep fragmentation and oxygen deprivation due to obstruction of the floppy portion of the upper airway (pharynx) d ....Many diseases that effect the respiratory system have their primary effect on the lungs and airway themselves but in some conditions, such as obstructive sleep apnea (OSA) and asthma, increased breathing load can induce periods of low blood oxygen which could further contribute to morbidity in these diseases. OSA is a disorder associated with snoring. Patients experience periods of sleep fragmentation and oxygen deprivation due to obstruction of the floppy portion of the upper airway (pharynx) during sleep. It affects 4% of men and 2% of women and causes excessive daytime sleepiness leading to increased risk of accidents, high blood pressure and premature cardiovascular disease. Asthma produces airway inflamation and narrowing and affects a wide range of people. Both OSA and asthma are associated with episodes of impaired breathing and reduced levels of oxygen in the blood. Low levels of oxygen in the blood (hypoxia) is well known to impair functioning of the central nervous system. We have recently found that hypoxia blunts sensations of increased breathing load in healthy people and in asthmatics. Hypoxia might therefore contribute to worsening of attacks in these diseases. This study aims to investigate how changes in blood oxygen levels affect brain processing of respiratory signals, how this translates to perception of sensations and the physiological adaptations that people make to cope with increased breathing load. We will also investigate whether the inhibitory effects of hypoxia on central nervous system function extend to other vital protective respiratory reflexes such as cough, awakening from sleep to increased breathing load and upper airway reflexes that are important for maintaining an open airway.Read moreRead less
Defining The Molecular Effectors Of Gene/environment Interaction On Mouse Heart Development
Funder
National Health and Medical Research Council
Funding Amount
$749,271.00
Summary
One third of all birth defects involve the heart, and are the most common cause of infant death. Some defects are due to genetic factors, but others arise when the pregnant mother is exposed to environmental stress. We will examine how one stress (low oxygen levels) causes abnormal heart formation in the embryo, look at what causes this at a molecular level, and explore if such stress increases the risk of heart defects in families with a history of such abnormalities
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 Effect Of Smoking On The Exacerbation Of Stroke: Oxidative Stress Involvement And Cerebrovascular Response.
Funder
National Health and Medical Research Council
Funding Amount
$292,216.00
Summary
This grant addresses whether smoking contributes to the severity of stroke outcome. The studies outlined in this proposal will contribute significantly in our understanding of how smoking contributes to the progression of stroke. The understanding of the involvement of smoking in the progression of stroke will be of great benefit in the development of improved stroke patient management.