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Creatine Synthesis And Transport In The Fetus - Critical Regulation Of Energy Supply For Fetal Growth & Survival?
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
Survival at birth depends on the baby being able to breathe effectively, to maintain adequate blood flow to every organ, and for the brain to coordinate these activities. Failure of any one of these will result in death. In this application we propose that the ability of the fetus and newborn baby to obtain adequate supplies of CREATINE is essential for survival, because this substance is essential for maintaining energy turnover in all cells in the body. In the adult, CREATINE is obtained eithe ....Survival at birth depends on the baby being able to breathe effectively, to maintain adequate blood flow to every organ, and for the brain to coordinate these activities. Failure of any one of these will result in death. In this application we propose that the ability of the fetus and newborn baby to obtain adequate supplies of CREATINE is essential for survival, because this substance is essential for maintaining energy turnover in all cells in the body. In the adult, CREATINE is obtained either from the diet (after absorption from the gut), or after synthesis in, and release from the liver. We do not know how fetal tissues obtain CREATINE, but we do know that when CREATINE is too low the fetus is likely to die, and that if extra CREATINE is supplied in the mother's diet the fetus is more likely to survive profound asphyxia at birth. In this project, in pregnant animals we will determine if fetal tissues can synthesize and take up CREATINE, and if providing extra CREATINE in the maternal diet throughout pregnancy can protect the heart, brain and breathing apparatus from the damaging effects of asphyxia or low oxygen (hypoxia). If successful, we will have developed a new treatment for pregnant women that protects their unborn baby from the dangers of birth asphyxia.Read moreRead less
Improving The Neonatal Transition In Infants With A Congenital Diaphragmatic Hernia
Funder
National Health and Medical Research Council
Funding Amount
$551,644.00
Summary
Congenital diaphragmatic hernia is a common congenital abnormality and occurs when the diaphragm fails to separate the abdominal and thoracic compartments before birth. This prevents the lung from growing properly and so at birth, the lung is unable to take over the role of gas exchange without considerable assistance. As a result, these infants are at high risk of death or significant disability and this application is focused on improving care and reducing morbidity in these infants.
Genetic Autopsy Of Perinatal Death: Diagnosis And Discovery By Genome Sequencing
Funder
National Health and Medical Research Council
Funding Amount
$989,332.00
Summary
Stillbirth, miscarriage and genetic termination of pregnancy are common and traumatic events. Despite medical investigation, many of the causes of these events are unexplained. This project plans to employ the latest in whole genome sequencing and functional modelling to explain these occurrences as well as lead to an increase in knowledge of genetics and development.
Preclinical Development Of TLR Signalling Inhibitors For Prevention Of Preterm Labour And Fetal Inflammatory Injury
Funder
National Health and Medical Research Council
Funding Amount
$690,821.00
Summary
Preterm birth affects 8% of Australian births and is a major cause of infant and child health problems. Therapies to prevent or delay prematurity are urgently required. This study will investigate new drugs that suppress the triggers of preterm labour. We will evaluate drug effects in mice and human placental tissue, to demonstrate safety and fetal protection from inflammatory injury that occurs with prematurity. Successful completion of the study is expected to lead to clinical trials in women.
Identifying And Preventing Inflammation-induced Brain Injury In Preterm Infants
Funder
National Health and Medical Research Council
Funding Amount
$338,652.00
Summary
Exposure to infection/inflammation around the time of birth is one of the most common factors associated with long-term disability. There is no effective treatment. My studies will use world-class techniques for measuring brain structure and function to improve our understanding of how infection/inflammation impacts on development of the preterm brain and determine whether blocking key inflammatory pathways in the brain will help restore normal brain growth and development in preterm infants.
Regulation Of Eicosanoid Production In The Fetal Placenta In Preterm Labour
Funder
National Health and Medical Research Council
Funding Amount
$256,980.00
Summary
Prostaglandins are fatty substances made within the body and they are what causes the pregnant uterus to contract and push out the fetus. At present we can't control preterm birth because we don't understand well enough how prostaglandin synthesis is controlled. New discoveries in our lab have suggested an exciting new possibility- that prostaglandins partially regulate their own synthesis. If we find this is so, there may be far-reaching implications for the ways in which anti-inflammatory drug ....Prostaglandins are fatty substances made within the body and they are what causes the pregnant uterus to contract and push out the fetus. At present we can't control preterm birth because we don't understand well enough how prostaglandin synthesis is controlled. New discoveries in our lab have suggested an exciting new possibility- that prostaglandins partially regulate their own synthesis. If we find this is so, there may be far-reaching implications for the ways in which anti-inflammatory drugs are used, not only in prevention of premature birth, but in inflammatory diseases too. Most research in this area has been directed toward understanding what controls the overall synthesis of prostaglandins, but there are several types of prostaglandins with different functions. we are now in a position to study, for the first time, how the synthesis of the specific prostaglandins is regulated in the pregnant uterus and how this changes during normal and preterm birth.Read moreRead less
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
Cell Therapy For Prevention Of Perinatal Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$539,337.00
Summary
Exposure of babies to infection or inflammation before birth 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. There is no treatment for the underlying inflammation and no way to prevent or treat the lung disease that it causes. This project will investigate a new stem-cell based treatment for lung inflammation that may prevent ....Exposure of babies to infection or inflammation before birth 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. There is no treatment for the underlying inflammation and no way to prevent or treat the lung disease that it causes. This project will investigate a new stem-cell based treatment for lung inflammation that may prevent life-threatening lung disease in preterm babies.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 And Neonatal Therapy To Improve Perinatal Outcome And Long-term Neurodevelopment
Funder
National Health and Medical Research Council
Funding Amount
$214,032.00
Summary
I am a consultant neonatologist with a half-time research appointment. Preventing perinatal morbidity and mortality is one of the greatest challenges in medicine today. My vision is to lead research into new fetal and neonatal therapies, foster collaborations with clinicians and scientists, and improve clinical practice. The scope of my research includes “brain-oriented” program of neonatal intensive care, neuroprotective strategies, and devising new fetal together with the obstetricians.