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Lay summaries are provided below of the Research Grants given in 2019.
Associate Professor Martha Lappas, Dr. Carlos Salomon, Dr. Alexis Shub, Dr. Harry Georgiou
Mercy Hospital for Women
(Sum provided $105,575)
Diabetes is one of the most challenging health problems in the 21st century. Diabetes is recognised as the world’s fastest growing chronic condition. It is estimated that between 2010 and 2030, there will be a 69% increase in numbers of adults with diabetes in developing countries and a 20% increase in developed countries. Type 2 diabetes is a major cause of morbidity and death worldwide. Complications from diabetes, including coronary artery and peripheral vascular disease, stroke, diabetic neuropathy, amputations, renal failure and blindness, results in increasing disability, reduced life expectancy and enormous burden on health care systems. One important strategy for tackling the diabetes burden is to screen for undiagnosed diabetes and for the future risk of developing diabetes. Early diagnosis of diabetes will significantly improve therapeutic strategies and overall health span.
It is now recognised that gestational diabetes mellitus (GDM) is an important predictor of the development of type 2 diabetes. In this study, we will use our well-characterised cohort of samples from the Mercy GDM Follow-Up study to determine if we can identify biomarkers to predict the development type 2 diabetes in women with previous GDM.
To view the abstract click here
Professor Euan M. Wallace AM, Dr Sarah A. Marshall
Monash Health
(Sum provided $21,700)
We seek to develop a new and better treatment for preeclampsia. About 1 in 20 pregnant women will develop preeclampsia. It is unique to pregnancy and is a disease of high blood pressure, kidney and liver damage. It is a major cause of maternal ill health and, because the only cure for preeclampsia is delivery of the placenta and therefore the baby, it is a leading cause of premature birth. Despite our best efforts, there is still much to do in lessening the burden of this disease for these women and their babies. To lessen this burden, there is a pressing need for more effective treatments for women with preeclampsia. That is what our research is about. We seek to develop a treatment for preeclampsia that directly targets the mother’s blood vessels.
In this project we will assess the beneficial effects of a broccoli sprout extract, known as BroccoMax®. This nutritional supplement is high in the antioxidant sulforaphane. Sulforaphane has been extensively studied in the field of cancer research, and has been trailed in numerous clinical trials around the world, establishing its safety. This study will now further assess the ability for sulforaphane to have beneficial cellular and vascular effects, and to begin the clinical translation by completing a pilot trial in women with preeclampsia to establish a suitable dose for a future large clinical trial.
Dr Roxanne Hastie
Mercy Hospital for Women
(Sum provided $38,410.46)
Preeclampsia is a serious pregnancy complication claiming the lives of 60,000 mothers annually, with no cure. We have found two potential treatments for this disease, metformin and proton pump inhibitors, which are already safely used during pregnancy for other complications.
In this project we will use the national health database of Scotland to investigate the incidence of preeclampsia among women who have taken metformin or proton pump inhibitors during pregnancy. If, as expected, preeclampsia is reduced among these women this will provide further evidence for the use of metformin and proton pump inhibitors to treat and/or prevent preeclampsia.
Dr Roxanne Hastie
Mercy Hospital for Women
(Sum provide $49,556.50)
Maternal mental health is becoming increasingly recognised as an area of unmet need during pregnancy, with an alarming 15-40% of pregnant women suffering from emotional difficulties.
It is therefore unsurprising that prescription of drugs to treat psychiatric disorders, including antidepressants, antipsychotics and mood stabilisers, during pregnancy has greatly increased over the last 30 years. However, little is known about the effects of these drugs on placental, fetal and newborn outcomes, with limited reporting and inconsistent findings.The placenta is the lifeline of a continuing pregnancy, providing oxygen and nutrients to the growing fetus, as well as allowing many drugs, including antidepressants, antipsychotics and mood stabilisers, to freely cross the placenta and potentially affect fetal development.
Alteration or dysfunction of the placenta can result in demise of pregnancy and a number of pregnancy complications, including fetal growth restriction and stillbirth. Thus, it is surprising that little is known about the effects of antidepressants, antipsychotics and mood stabilisers on placental function as well as the levels transferred through the placenta to the fetus.
Due to this scarcity of data, medical management of psychiatric disorders during pregnancy presents as a significant challenge for both clinicians and patients, with the difficulties of balancing the health of the mother with that of the fetus. Improved characterisation of a broad spectrum of antidepressants, antipsychotics and mood stabilisers on placental function and the levels of exposure to the fetus may help inform clinicians about the risks and fetal exposure of these medications during pregnancy – which is the focus of this application.
We have identified a panel of 22 relevant antidepressants, antipsychotics and mood stabilisers, which are commonly prescribed during pregnancy. Using these therapeutics, we will be investigating:
1. The effect on human placenta function after exposure.
2. The concentration of drugs transferred to the fetus among women who have taken these medications during pregnancy.
During this investigation human placental tissue will be collected from healthy women at the time of delivery, placental cells will be isolated, treated with therapeutics and placental function measured using an array of laboratory experiments. Additionally, we will collect
placental tissue and blood from the umbilical cord at the time of delivery from women who have taken any of these medications throughout pregnancy. Using umbilical cord blood, we will be able to determine the concentration of drugs transferred from the mother to the fetus, giving an estimate of fetal exposure to these medications. Additionally, we will also characterise the placental function of these women.
Dr Tu’uhevaha Kaitu’u-Lino
Mercy Hospital for Women
(Sum provided $37,101)
Fetal Growth Restriction and Preeclampsia are two of the most serious complications of pregnancy, responsible for significant fetal and maternal death and disability. Fetal growth restriction refers to a fetus that fails to reach its genetic growth potential during pregnancy. It occurs as a result of placental insufficiency – when a placenta fails to deliver adequate blood supply, oxygen and nutrients to nourish the growing baby. Sadly, fetal growth restriction is the leading cause of stillbirth, a tragedy that affects 1:130 pregnancies in Australia.
Preeclampsia is a disease that begins early in pregnancy as a result of the placenta failing to establish correctly. The poorly formed preeclamptic placenta fails to obtain adequate blood supply to support the infant and as a result, releases toxins into the mother’s blood stream. The toxins move around the mother’s blood stream causing damage to her blood vessels and major organs. It is typically diagnosed only after the woman presents with signs such as high blood pressure and protein in her urine.
Diagnostics for prediction of both of these diseases are desperately lacking, limiting the capacity for clinicians to intervene and improve outcomes for mothers and their babies.
Our team have spent the last 2 years working towards developing a blood test that could predict which women/babies are at risk of fetal growth restriction and preeclampsia. We have identified a number of useful genetic (mRNA, miRNA) and protein markers within the mother’s blood that are dysregulated before clinical diagnosis of either fetal growth restriction or preeclampsia. Thus, we are making significant and exciting progress towards our goal.
In this application, we propose undertaking elemental metabolomics. This will allow us to determine whether there is an altered elemental profile within the circulation of women preceding their diagnosis of fetal growth restriction or preeclampsia. If we can identify an altered elemental signature, we could use this information to contribute towards a multimarker blood test for prediction of these diseases.
Dr Fiona Brownfoot, Associate Professor Greg O’Grady
Mercy Hospital for Women
(Sum provided $48,600)
We are developing a device that continuously and accurately assesses fetal distress in labour. With the generous funds of the Norman Beischer Medical Research Foundation we have promising data to validate our sensor. In this application we will use rapid prototyping and 3D printing technology to produce a device that will house and protect our sensor.
Fetal asphyxia is a leading cause of seizures, cerebral palsy, stillbirth and death of newborns at team. It occurs due to the uterine contractions of labour limiting blood flow and oxygen delivery to the fetus. If the fetus becomes hypoxic it can lead to brain injury and death. If fetal distress is identified early, then the baby can be swiftly delivered, avoiding these devastating complications.
Currently we use a heart rate monitor (cardiotocography CTG) to determine whether the baby is coping with labour. The CTG is often difficult to interpret and inaccurate. To improve our assessment of fetal distress we perform fetal scalp pH or lactate sampling. This involves using a scalpel to incise the fetal scalp and collect a blood sample to measure pH or lactate. This is a very invasive procedure and should only be performed sparingly. Furthermore it only tells us how the baby is coping at the time it is taken and we can miss the critical point when the baby needs delivery.
The optimal way to detect fetal asphyxia in labour is to accurately and continuously measure a direct marker of fetal distress and we are developing this device. We have validated our sensor and we are now ready to create our device. Using rapid prototyping technologies and 3D printing we will develop our application device.
This device has the potential to transform monitoring in labour and reduce brain injury and death of babies at term.
Babies who are newly born or less than 28 days old are at a high risk of developing serious infections. When a baby develops a serious infection, this is referred to as neonatal sepsis. This condition affects several million babies around the world each year, and is one of the top three reasons that babies die before they are a month old.
Neonatal sepsis is difficult to diagnose, even for experts. At an early stage, the signs of infections in babies are very similar to other more common problems that are not infections. However, without early treatment, an infection can be lethal for a baby. This means that some babies die due to not having early treatment for their infection. It also means that many babies who do not actually have infections end up receiving antibiotics anyway as it is difficult for doctors, nurses and midwives to work out whether they are in the early stages of an infection. In fact, the great majority of babies who are prescribed antibiotics do not actually have an infection. Antibiotics are vital when a baby really does
have an infection. However, antibiotics involve some discomfort (they need one or more injections) and have some risks (potentially serious side-effects and promoting drug resistance), so they should ideally only be used when there really is an infection.
Many researchers and doctors who care for babies have suggested that a simple and rapid test done at the baby’s bedside that indicates whether a baby is in the early stages of an infection would greatly help with this problem – enabling early effective treatment for serious infections and preventing over-use of antibiotics. This type of test is called a ‘point of care test’, and none exists for neonatal infections.
This study is designed to work out how a combination of two new tests could be developed into a point of care test to help doctors, nurses and midwives identify infections at an early stage in babies. The two new tests the study will look at are both related to neutrophils – cells in the blood that fight infection. The study will include a group of babies
who are unwell in hospital with a possible infection. Each of these babies will have the combination of two new tests checked on blood that is left over from samples already collected for a routine test. We will observe these babies over time to work out which babies really do have an infection and which babies have another reason for their symptoms that is not an infection. We will compare the results of the combination of the two tests between the babies who had infections and the babies who did not have infections. This way, we will be able to work out whether this new test combination is a reliable and accurate way to identify infections in babies at the very start of their illness.
Jacqueline Donoghue
Royal Women’s Hospital
(Sum provided $61,599)
Endometriosis, defined as the growth of hormonally responsive endometrial tissue outside of the uterine cavity, is an estrogen-dependent, chronic, pro-inflammatory disease that develops in 6-10% of women of reproductive age. Symptoms include chronic pelvic pain, dysmenorrhea and subfertility. Current therapeutic interventions include hormonal approaches non-steroidal anti-inflammatory medication and surgery. In Australia, the direct medical and surgical costs for endometriosis have been estimated at $6 billion per annum for adult women and $600 million for adolescent girls. Despite this impact on women’s health and quality of life, there remains significant unmet need for new treatments that provide efficacy and have favourable long-term safety profiles.
New drug development is expensive and can take up to 14 years before clinical trial. However, systematic high throughput screening (HTS) and high content imaging of pre-existing clinically approved drugs can accelerate drug discovery and clinical translation where the combination of automation, imaging of large compound libraries can identify drugs with significant effects in disease-relevant cell-based assays.
We have now screened >3,800 clinically approved drugs using three immortalised human endometriosis endometrial cell lines using a HTS technology. From our initial analysis, 2.4% of drugs (92/3840) were identified for their ability to significantly interfere with estrogen stimulation of cell growth with 10 drugs or 0.26% inhibiting growth by more than 70%. These drugs included antibiotics, pain suppressors, epigenetic modifiers and anti-cancer small molecule inhibitors.
We have selected 5 drugs from this list that are likely to be suitable for repurposing and are performing preclinical validation assays to determine their suitability for clinical translation. This validation process will involve high-throughput cell based functional assays and mechanistic studies for each drug on 9 patient derived endometriosis endometrial cells. The findings from these studies will demonstrate suitability for repurposing and clinical translation in the future.
Dr Natalie Hannan, Dr Teresa MacDonald, Dr Tu’uhevaha Kaitu’u-Lino PhD, Professor Stephen Tong MBBS, PhD
Mercy Hospital for Women
(Sum provided $34,644)
Preeclampsia and fetal growth restriction are highly serious complications of pregnancy, especially since they are responsible for major proportions of fetal and maternal death and disability. Preeclampsia is a disease that is diagnosed during the second half of pregnancy and affects around 3-8% of all pregnancies. When a fetus fails to reach its full growth potential during pregnancy, this is referred to as fetal growth restriction (FGR).
Both of these hideous complications are the result of placental insufficiency – which is thought to result from poor development of the placenta very early in pregnancy. The placenta simply fails to adequately tap in to the mother’s blood supply to support and nourish the infant. Thus the infants growth is stunted and development is compromised. It is therefore understandable that placental insufficiency and FGR is the leading cause of stillbirth, affecting every 1:130 pregnancies in Australia and far higher rates in the developing world.
In the case of preeclampsia the dysfunctional preeclamptic placenta releases excessive levels of toxins into the mother’s blood stream. These toxins move around the mother’s blood stream causing injury and constriction of her blood vessels and major organs. This causes an increase in her blood pressure and shutdown of her organs. Preeclampsia is traditionally picked up if the mother presents with signs of high blood pressure and high levels of protein in her urine.
There are enormous healthcare costs associated with the immediate consequences (neonatal and maternal intensive care), and the risk of disability and death. Furthermore women who have had preeclampsia have an increased risk of cardiovascular disease following pregnancy. Earlier intervention and management would have profound benefits for both mothers and their babies.
Diagnostics for prediction of both of these diseases are desperately lacking, limiting the capacity for clinicians to intervene and improve outcomes for mothers and their babies.
A protein known as endothelin-1 (ET-1) is thought to play a role in preeclampsia and the high blood pressure observed in this condition, as it causes blood vessels to constrict. We have already identified that women with preeclampsia have very high levels of ET-1 in their blood. We have also observed in a small cohort of women, high levels of ET-1 in the mother’s blood before any diagnosis of preeclampsia and FGR.
In this application, we propose to examine two prized cohorts of bloods collected from women who went on to develop preeclampsia and/or FGR, before diagnosis. This will allow us to determine whether ET-1 levels are elevated in women preceding their diagnosis of preeclampsia or FGR. If we can identify ET-1 is increased in the very early stages we could use ET-1 as an early marker blood test for prediction of preeclampsia and/or FGR.
Additionally proving excess production of ET-1 in the maternal blood stream precedes diagnosis, there may be future scope to target therapies to reducing the excess ET-1 in these diseases.
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Account Name: Norman Beischer Medical Research Foundation
Bank: Bendigo
BSB: 633000
Account No: 5529128
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