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.
Over the next five years, I will further expand and continue to translate my basic and clinical research programs in women’s health to deliver outcomes to the Australian and international health care systems. In particular, I will target the concept of pregnancy as a determinant of future community health and wellbeing. There is now substantial consensus that environmental influences (including, but not limited to, maternal nutrition) during early life can have a fundamental impact on human deve ....Over the next five years, I will further expand and continue to translate my basic and clinical research programs in women’s health to deliver outcomes to the Australian and international health care systems. In particular, I will target the concept of pregnancy as a determinant of future community health and wellbeing. There is now substantial consensus that environmental influences (including, but not limited to, maternal nutrition) during early life can have a fundamental impact on human development, with consequences for biological and social function and behaviour throughout the lifecourseRead moreRead less
Differential Effects On Fetal Growth And Development Of Repeated Fetal Or Maternal Corticosteroid Treatments
Funder
National Health and Medical Research Council
Funding Amount
$356,849.00
Summary
Injections of synthetic hormones (corticosteroids) to women at risk of early preterm birth reduce the rate of respiratory illness and death in the newborn infant. It is standard clinical practice prior to early preterm birth to give corticosteroids by intramuscular injection to the mother. For many women, however, preterm birth does not occur as expected and it has become common practice to give repeated courses of corticosteroids to women in whom the risk of preterm delivery recurs or continues ....Injections of synthetic hormones (corticosteroids) to women at risk of early preterm birth reduce the rate of respiratory illness and death in the newborn infant. It is standard clinical practice prior to early preterm birth to give corticosteroids by intramuscular injection to the mother. For many women, however, preterm birth does not occur as expected and it has become common practice to give repeated courses of corticosteroids to women in whom the risk of preterm delivery recurs or continues. Using the sheep model, we have shown that repeated doses of corticosteroids, given intramuscularly to the mother, are of benefit to newborn lung function, but also reduce the rate of fetal growth and adversely affect brain development. Evidence from the Western Australian Preterm Infant Cohort Study suggests that birthweight in humans is similarly affected by repeated corticosteroids and is followed by behavioral disorders in childhood. Using sheep, we have shown that repeated injections of corticosteroids given directly to the fetus cause no reduction in birthweight although maturation is still enhanced. This finding of a differential effect of corticosteroids by different routes of administration raises several exciting opportunities and questions. First is the possibility that direct fetal treatment may be of use in humans, if current human trials show that repeated doses cause effects similar to those we have seen in sheep. Secondly, the finding challenges our current understanding of how an individual may be programmed for subsequent health or illness by prenatal events. The proposed study will attempt to explain why corticosteroids given to the mother, but not the fetus, restrict fetal growth. Our hypothesis is that these hormones, when given repeatedly to the mother, adversely affect the ability of the placenta to transfer essential nutrients to the fetus. We will test this hypothesis using pregnant sheep in which catheters have been implanted surgically.Read moreRead less
I am a general paediatrician involved in national epidemiological and clinical research about a range of childhood conditions in Australia. I also have expetise in research translation into the
Who determines gestation length - mother or fetus? This project will extend our knowledge of a key biological process - pregnancy. Variation of gestation length by 10% is generally deleterious to the offspring, and smaller babies have been shown to be more susceptible to later life diseases. Therefore, extension of the information gained from this project will likely impact researchers in species conservation, pest control, and the livestock industries, as well as human, obstetric care and pract ....Who determines gestation length - mother or fetus? This project will extend our knowledge of a key biological process - pregnancy. Variation of gestation length by 10% is generally deleterious to the offspring, and smaller babies have been shown to be more susceptible to later life diseases. Therefore, extension of the information gained from this project will likely impact researchers in species conservation, pest control, and the livestock industries, as well as human, obstetric care and practice. Specifically, knowledge gained from this project may lead to means of limiting (pest control) as well as enhancing (endangered species) species survival.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
Impact Of The Extraembryonic Tissues On Early Embryonic Development: Genetic Basis Of Abnormal Body Plan
Funder
National Health and Medical Research Council
Funding Amount
$316,326.00
Summary
An important milestone of early development is the attachment (or implantation) of the embryo to the wall of the womb through the action of a specialized population of cells known as the trophoblasts. The early conceptus comprises not only cells that make up the embryo but also those (called extraembryonic cells) that later forms the placenta, and the membranes that wrap around the developing fetus. The placenta and the membranes are indispensable for the normal fetal growth by providing the eff ....An important milestone of early development is the attachment (or implantation) of the embryo to the wall of the womb through the action of a specialized population of cells known as the trophoblasts. The early conceptus comprises not only cells that make up the embryo but also those (called extraembryonic cells) that later forms the placenta, and the membranes that wrap around the developing fetus. The placenta and the membranes are indispensable for the normal fetal growth by providing the effective nourishment and protection for the developing fetus. Recent studies in the mouse have revealed that normal development of the recently implanted conceptus depends on the reciprocal interaction of the embryonic and extraembryonic cells. Abnormal embryo may form if the non-embryonic cells do not differentiate normally, as seen in the situation when an X-chromosome is lost from the female embryo (as in 45X0 Turner syndrome) and in early conceptus that carries a gene mutation that affects the production of growth factors by the extraembryonic cells. Functional deficiency of the extraembryonic cells might be a cause for early pregnancy loss where the conceptus has successfully implanted but the embryo fails to form. The remarkable conservation of the molecular mechanism that controls mammalian development allows us to use the mouse embryo as a genetic model for human development. The proposed project is designed to examine in a laboratory mouse model the molecular and cellular factors that regulate the activity of the extraembryonic cells. Specifically, we focus on a gene known as Sox17, which may be involved with the differentiation of the extraembryonic cells. We will study the impact of the mutation of this gene on the development of the early embryo to test the hypothesis that the extraembryonic cells may fulfill an important function in ensuring normal embryo formation, in addition to the other roles of nourishment and mechanical protection of the fetus.Read moreRead less