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MECHANISMS OF ABNORMAL EXPRESSION OF THE IGF2 GENE IN DISORDERS AFFECTING FOETAL GROWTH
Funder
National Health and Medical Research Council
Funding Amount
$560,434.00
Summary
The IGF2 gene is crucial for foetal growth. Only the copy inherited from the father is active, a phenomenon named parental imprinting. In some children with foetal overgrowth or growth retardation, the deregulation of imprinting of the IGF2 gene during the first days of foetal development will influence subsequent growth and will also have major implications in post-natal and adult life. We will investigate the mechanisms resulting in abnormal imprinting of the IGF2 early in development.
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
A small number of babies die unexpectedly while still in the womb: the numbers are much higher than those dying from Sudden Infant Death Syndrome (SIDS). Some of these babies slow their movements down in the days before death. It would be very helpful to be able to accurately monitor babies' movements in the womb so that we could help the few babies who need it, and so prevent poor outcomes. Mothers feel their babies moving, but it's often hard for them to pick up all the movements that do occur ....A small number of babies die unexpectedly while still in the womb: the numbers are much higher than those dying from Sudden Infant Death Syndrome (SIDS). Some of these babies slow their movements down in the days before death. It would be very helpful to be able to accurately monitor babies' movements in the womb so that we could help the few babies who need it, and so prevent poor outcomes. Mothers feel their babies moving, but it's often hard for them to pick up all the movements that do occur. The best way of measuring babies' movements is during an ultrasound. However, that's expensive and means that the pregnant mother needs to lie still for about half an hour to have this testing done. We are developing a way of recording babies' movements, which still lets the pregnant woman continue with her normal activities. We will do this using an AMBULATORY FETAL ACTIVITY MONITOR, which is an accelerometer, like an advanced pedometer. The ambulatory fetal activity monitor will measure the activity of the unborn baby during pregnancy, looking at the number of times s-he moves and how simple or complex the movements are. We expect that the unborn baby who is not getting enough nutrition during the pregnancy will have fewer movements than other unborn babies. This project involves checking that movements picked up by the ambulatory fetal activity monitor are the same as movements seen on an ultrasound. We will then monitor a large number of pregnant women with healthy and possibly unhealthy babies, to help identify the babies who need help. Once we have this information, we will be able to use it in the future to possibly prevent poor outcomes in those babies who do need help.Read moreRead less
Defining Genetic And Epigenetic Variation During Early Development
Funder
National Health and Medical Research Council
Funding Amount
$996,075.00
Summary
We all began life with a set of genes inherited from our parents. However, it's now known that from the time we were in the womb onwards that genes can be turned off and on by the environment or even completely lost or gained. Even what your mother ate or how she behaved while she was pregnant could have influenced your future health. Because people are so different, we are studying the subtle differences between twins to tease out the factors that may influence our genes and our health.
Novel Therapy For Enhancing Organ Maturation In Pre-term Babies
Funder
National Health and Medical Research Council
Funding Amount
$694,323.00
Summary
This project is developing a factor to enhance organ maturation and repair that may provide a new therapy for premature babies and fetuses with birth defects. This exciting new finding allows for the development of treatments of underdeveloped organs, in particular the lungs of premature and growth restricted babies. We are also trialing this factor in unborn babies with defects to the kidneys and lungs of which there is currently no cure.
Environmental Influences In The Establishment Of The Epigenetic Landscape In Children
Funder
National Health and Medical Research Council
Funding Amount
$695,097.00
Summary
The DNA in each of our cells does not exist alone, it is packaged into complex structures called chromosomes, through association with many different proteins. The distribution of these proteins varies along the length of a chromosome depending on the type of cell and this phenomenon is called 'epigenetics', literally meaning 'above the DNA'. Epigenetic analysis is the study of how proteins and other molecules can change the activity of a gene without changing the DNA sequence. All of our cells ....The DNA in each of our cells does not exist alone, it is packaged into complex structures called chromosomes, through association with many different proteins. The distribution of these proteins varies along the length of a chromosome depending on the type of cell and this phenomenon is called 'epigenetics', literally meaning 'above the DNA'. Epigenetic analysis is the study of how proteins and other molecules can change the activity of a gene without changing the DNA sequence. All of our cells use epigenetic changes to help control how they grow and develop. Evidence suggests a direct link between diet and environmental influences on our epigenetic profile. Recent research has traced the origins of many of the health problems of adult life back to the earliest periods of development _ to the time spent in the womb and the first few years of life. If we are born with a low birth weight, we are more likely to get sick later in life. Overwhelming evidence exists that the environment in the womb is critical for a healthy birth weight (and health in later life) and it is thought that epigenetics may be the missing link between this environment, low birth weight, and therefore health in later life. In addition, mounting evidence supports a general link between epigenetic de-regulation and predisposition to disease. However, the timing and the overall contribution of environmental- genetic influences to the establishment of faulty epigenetic markings remain largely unknown. Twins are the best model to study this link as they share similar (but not identical environments) and some share identical genetic makeup. Using twins, Dr Jeffrey Craig and his team will investigate the factors in the prenatal environment that modify specific cells, leading to low birth weight and increase disease risk later in life. They predict that this occurs via specific changes in gene activity caused by epigenetic disruption.Read moreRead less
Vitamin D In Pregnancy And Growth Of The Offspring.
Funder
National Health and Medical Research Council
Funding Amount
$168,550.00
Summary
Vitamin D is a potent steroid hormone required for bone growth and mineralisation, and there is evidence that it regulates cell proliferation. Insufficiency in pregnant women is a cause for concern. The role of vitamin D in human fetal development has been little investigated. At the severe end of the maternal vitamin D insufficiency spectrum, a very small number of deficient neonates have congenital rickets. Low maternal vitamin D status has also been associated with neonatal hypocalcaemia and ....Vitamin D is a potent steroid hormone required for bone growth and mineralisation, and there is evidence that it regulates cell proliferation. Insufficiency in pregnant women is a cause for concern. The role of vitamin D in human fetal development has been little investigated. At the severe end of the maternal vitamin D insufficiency spectrum, a very small number of deficient neonates have congenital rickets. Low maternal vitamin D status has also been associated with neonatal hypocalcaemia and defective tooth enamel. Randomised trials have shown that giving vitamin D to deficient women significantly improves their offspring's birth size and length at a year of age, in one study even though all infants were given vitamin D supplements post-natally. We do not understand the nature of the relationship between maternal vitamin D status and offspring growth. There could be a continuous association, or a threshold vitamin D level below which offspring growth is impaired. If the latter is the case, that threshold value needs to be known. Furthermore, we do not know whether maternal vitamin D level in early or late gestation is most influential in terms of fetal and infant growth. Raised maternal parathyroid hormone (PTH) level is a marker of disturbed vitamin D metabolism. There is evidence that offspring are shorter with increasing level of maternal PTH. In a study in Geelong, 63% of 20-45 year old women tested in winter, and 32% tested in summer, had vitamin D levels in the range where PTH rises. Thus a significant proportion of women may have insufficient vitamin D, in early or late pregnancy, to sustain optimal fetal growth. These issues are important for the health of mothers and their offspring, and there are public health implications, in terms of maternal health and possibly later health of the offspring. These issues have not been investigated in Australia or elsewhere, and this is a novel and important study.Read moreRead less