Achieving Targeted Delivery Of Drugs To Uterine Muscle In Women For The Prevention Of Preterm Labour
Funder
National Health and Medical Research Council
Funding Amount
$469,008.00
Summary
We have patented liposomes targeted to the uterus, which enable us to deliver drugs specifically to the muscle cells of the uterus, increasing safety. The liposomes can be loaded with drugs that either block or promote contractions, creating a versatile drug delivery system that could treat premature labour or postpartum haemorrhage which are major clinical problems. We seek support to demonstrate their effectiveness in mouse and primate models of preterm labour prior to human studies.
Antagonist Of Corticotrophin Releasing Hormone As Therapeutic Agents For The Prevention Of Premature Birth In Humans
Funder
National Health and Medical Research Council
Funding Amount
$376,650.00
Summary
In developed countries the most common cause of the death of a newborn baby is premature delivery. Pre-term delivery remains the greatest cause of neonatal mortality in the western world and a major consumer of health dollars (approx. $5-7B per year in the US alone). However, a delay in the onset of labour from 20 to 25 weeks has been shown to result in a 55% greater probability of infant survival (550 fewer deaths per 1000). This project will allow: The development of new drugs that will allow ....In developed countries the most common cause of the death of a newborn baby is premature delivery. Pre-term delivery remains the greatest cause of neonatal mortality in the western world and a major consumer of health dollars (approx. $5-7B per year in the US alone). However, a delay in the onset of labour from 20 to 25 weeks has been shown to result in a 55% greater probability of infant survival (550 fewer deaths per 1000). This project will allow: The development of new drugs that will allow the extension of pregnancy term The development of protocols that will in turn reduce neonatal mortality. Additionally we believe that these new agents will be useful in preventing the onset of labour after fetal surgery. Currently there are no effective treatments capable of substantially changing delivery dates. Available therapeutics delay the onset of labour, at best, 24 hours. However, recent exciting results from our laboratories show that rising concentrations of the placental peptide Corticotrophin Releasing Hormone (CRH) are associated with the onset of labour. Further, we have also delayed the onset of labour in pregnant sheep by infusing a relatively insoluble CRH antagonist into the sheep fetus. Labour commenced ONLY AFTER the drug was withdrawn from the mother. This project builds upon an interdisciplinary team: medicinal chemists, molecular modellers, pharmacologists and endocrinologists, to further develop an exciting Australian discovery. Successful completeion of this research will, for the first time, allow the control of pregnancy duration MAXIMISING the benefits to mother and child, reducing mortality and later life morbidities typically associated with premature birth.Read moreRead less
Bronchopulmonary Dysplasia – A Regenerative Medicine Approach
Funder
National Health and Medical Research Council
Funding Amount
$480,406.00
Summary
Bronchopulmonary dysplasia is a major leading cause of morbidity and mortality in premature babies. There is no cure. We have previously shown that amnion epithelial cells can reduce the extent of lung damage during early stages of lung development. We aim to understand how amnion cells can promote repair by interacting with existing cell types in order to restore normal lung structure and function. The outcomes from this study will help design clinical trials and develop new therapies.
Second Trimester Intra-amniotic Treatment For Early Preterm Birth
Funder
National Health and Medical Research Council
Funding Amount
$392,420.00
Summary
Preterm birth is the leading cause of neonatal death and disability in Australia today, with those born before 32 weeks' completed gestation at the highest risk. Preventing these early preterm births requires treatment of the causative uterine infection. This proposal is to conduct the first study of direct intraamniotic antibiotic treatment of uterine Ureaplasma infection in a clinically relevant, large animal model of second trimester pregnancy.
Role Of Endogenous Opioid Peptides In Endometrial Receptivity And Placentation
Funder
National Health and Medical Research Council
Funding Amount
$523,884.00
Summary
Infertility affects 1 in 10 couples. In early pregancy miscarriage is the commonest complication resulting in the loss of 10-15% of all conceptions. During the latter part of pregnancy, complications such fetal growth restriction and preeclampsia, affects up to 10% of women resulting in considerable suffering to the mother and her newborn. Many of these births are premature with neonates requiring intensive care. There is also good evidence that children who are born prematurely with low birth w ....Infertility affects 1 in 10 couples. In early pregancy miscarriage is the commonest complication resulting in the loss of 10-15% of all conceptions. During the latter part of pregnancy, complications such fetal growth restriction and preeclampsia, affects up to 10% of women resulting in considerable suffering to the mother and her newborn. Many of these births are premature with neonates requiring intensive care. There is also good evidence that children who are born prematurely with low birth weight are much more likely to develop a host of diseases including cardiovascular disease, diabetes and obestiy in adult life increasing the long term burden of health care support. Infertility is often due to the lack of uterine endometrial receptivity while the pregnancy complications arise from the reduced growth of the placenta and sub-optimal interactions between the mother's uterus and the growing placenta. Endometrial infertility, placental growth and interactions with the endometrium is stringently regulated by substances produced at the maternal endometrial- placental interface. To understand how infertility and pregnancy complications arise, develop diagnostic, monitoring and therapeutic tests it is critical to understand the roles played by these regulatory substances. We have novel data suggesting that small proteins known as endogenous opioids could be enchancing endometrial receptivity and the growth and development of the placenta. Interstingly these substances are closely related to exogenous opioids such as heroin and morphine. We will investigate the manner in which these substances regulate endometrial immune cell function, maintain the endometrial stromal cell bed in preparation for pregnancy and direct the growth and differentiation of the placenta. The findings will give novel insights into infertility, improve the success rates of in vitro fertilization, reduce maternal and neonatal complications of pregnancy.Read moreRead less
This project will test if the ratio of the two different estrogens found in the blood of pregnant women is the critical factor in determining the onset of contractions in the uterus at labour. The studies will also determine the role of a newly discovered receptor for estrogens in allowing powerful contractions at labour. Results will allow development of new treatments to prevent premature birth that block the actions of estrogen at this new receptor or change the ratio of the two estrogens.
Regulation Of Progesterone Action In Human Parturition.
Funder
National Health and Medical Research Council
Funding Amount
$314,983.00
Summary
Premature birth is the leading cause of neonatal death and sickness, and numbers are increasing due to our ignorance of the biology of labour. Progesterone maintains pregnancy and its withdrawal results in birth, but how this is achieved in humans is unknown. This project will determine the molecular mechanisms by which progesterone action is regulated during the transition from pregnancy to birth. This data will guide new strategies to prevent premature birth.
Novel Methods For Early Bedside Detection And Prognosis Of Preterm Brain Injury
Funder
National Health and Medical Research Council
Funding Amount
$630,880.00
Summary
Quick and robust assessments of preterm brain activity are critical for identifying early markers of brain injuries. We need to predict poor outcomes before they develop in order to give clinicians the best chance of helping sick infants. This project will develop and validate new non-invasive methods for assessing early brain activity in preterm infants at risk of developing poor neurodevelopmental outcomes.
Regulation Of Prostaglandin Endoperoxide Synthase-2 In The Human Fetal Membranes At Birth
Funder
National Health and Medical Research Council
Funding Amount
$249,750.00
Summary
Preterm birth with the resulting immaturity of babies is the leading cause of death and disease among newborns. Early birth occurs in 6 to 11% of pregnancies, and its rate is slowly increasing in industrialized countries. We need a much better knowledge of the regulation of the parturition process to find ways to reverse this trend. Prostaglandins are hormonal substances that stimulate uterine contractions, cervical dilatation and membrane rupture. Intrauterine tissues produce prostaglandins, an ....Preterm birth with the resulting immaturity of babies is the leading cause of death and disease among newborns. Early birth occurs in 6 to 11% of pregnancies, and its rate is slowly increasing in industrialized countries. We need a much better knowledge of the regulation of the parturition process to find ways to reverse this trend. Prostaglandins are hormonal substances that stimulate uterine contractions, cervical dilatation and membrane rupture. Intrauterine tissues produce prostaglandins, and an increase of prostaglandin levels in the uterus is likely responsible for inducing labour both normally and preterm. We have previously identified an enzyme protein in the fetal membranes, called prostaglandin synthase-2, that has a key role in the synthesis of intrauterine prostaglandins during pregnancy. This enzyme is increasingly expressed before labour onset. In the present application, we propose studies to determine what causes the increased expression. We hypothesize that the gene encoding this enzyme is specifically activated in the fetal membranes in preparation for labour. We will define the mechanism of regulation by determining the activity of the gene in tissues from women who deliver either spontaneously or without labour at term and preterm. Further, we will determine the interaction of regulatory proteins with the prostaglandin synthase-2 gene in these pregnancies in order to understand the mechanisms of regulation at the molecular level. Finally, we will conduct cell culture studies to experimentally manipulate prostaglandin synthase-2 gene activity in fetal membrane cells. As an overall outcome of this work, new targets may be identified for drugs to disrupt prostaglandin synthase-2 gene activation specifically in the fetal membranes. The long term perspective is to block prostaglandin synthesis in the uterus in order to suppress preterm labour and prevent preterm birth.Read moreRead less
We aim to predict neurodevelopmental disability in babies born very preterm, earlier and more accurately than currently possible, by identifying structural and functional connectivity features that correlate with clinical measures of motor and neurodevelopmental functions. To do this we will use brain magnetic resonance imaging (MRI), dense array electroencephalography (EEG) and structured clinical neurodevelopmental assessments to provide a cutting edge view of the state of brain development.