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
FETAL ORIGIN OF ADULT DISEASE? A POPULATION-BASED STUDY OF THE OFFSPRING OF WOMEN WITH SEVERE MENTAL DISORDERS
Funder
National Health and Medical Research Council
Funding Amount
$442,875.00
Summary
Fetal origin of adult disease is a currently influential paradigm in epidemiological research into common diseases (ischaemic heart disease, hypertension, diabetes) and behaviour problems (suicide, criminal offending). It postulates an early pathophysiological programming of outcomes that become manifest in adult life. In the proposed research we aim to examine key aspects of this model by conducting a population-based study on the developmental outcomes, antecedent and concomitant risk factors, ....Fetal origin of adult disease is a currently influential paradigm in epidemiological research into common diseases (ischaemic heart disease, hypertension, diabetes) and behaviour problems (suicide, criminal offending). It postulates an early pathophysiological programming of outcomes that become manifest in adult life. In the proposed research we aim to examine key aspects of this model by conducting a population-based study on the developmental outcomes, antecedent and concomitant risk factors, and a spectrum of neuropsychiatric morbidity in all children (N-5150) born in Western Australia in 1980-2001 to women diagnosed with schizophrenia, bipolar affective disorder or unipolar depression, as compared to children (N-504,553) born to women without a diagnosed psychiatric illness. The study will be based on record linkage, utilising the unique resource of multiple, comprehensive population databases in Western Australia. Specifically, this research will identify the range of developmental outcomes and morbidity in four consecutive birth cohorts (1980-84; 1985-89; 1990-94; and 1995-2001) of children at high genetic and environmental risk and examine their relationship to specific risk factors, including familial genetic load, obstetric complications, severity of maternal illness, and psychosocial adversity. The study will be the first of its kind and its findings will inform aetiological research into the major mental disorders, as well as clinical and public health practice. It will provide novel data on fundamental issues, such as the interaction between genetic risk and environmental factors in the causation of schizophrenia, as well as on the extent to which the risk of developing severe mental illness is immutably embedded in its fetal origin, or is modifiable by subsequent mitigating factors and appropriate intervention.Read moreRead less
Foetal Determinants Of Sleep Disordered Breathing In Infants
Funder
National Health and Medical Research Council
Funding Amount
$174,691.00
Summary
Obstructive sleep apnea (OSA) has been identified and recorded in infants, however the factors that lead to the development of OSA and its prevalence in infants is unknown. We have recorded OSA in some infants and we demonstrated that the severity of apnea was at its peak at approximately 2 months of age and then resolved by 1 year. We hypothesised that these infants possibly had a maturational delay of breathing control during sleep. This project is designed to examine the development and preva ....Obstructive sleep apnea (OSA) has been identified and recorded in infants, however the factors that lead to the development of OSA and its prevalence in infants is unknown. We have recorded OSA in some infants and we demonstrated that the severity of apnea was at its peak at approximately 2 months of age and then resolved by 1 year. We hypothesised that these infants possibly had a maturational delay of breathing control during sleep. This project is designed to examine the development and prevalence of sleep and breathing disorders in infants. The prenatal factors that possibly influence development of sleep and breathing disorders in infants, in particular, the effects of maternal smoking will be determined. Pregnant women will be recruited for the study during their third trimester. The foetal movements, foetal breathing movements, heart rate and sleep state will be monitored continuously overnight in the patients home between 32 and 36 weeks gestation using a newly developed foetal movement monitor. The infants will be subsequently studied using overnight polysomnography at 2 months of age to assess their breathing, sleep patterns, arousal behaviour, and the presence and severity of central and obstructive apnea. A group from these infants will be selected and studied longitudinally to examine the development of sleep and breathing disorders more closely. These infants will undergo overnight sleep studies during the first week of life, then at 2 and 6 months of age. A detailed medical history will also be collected regarding the pregnancy, the perinatal history of the infant, exposure to cigarette smoke during pregnancy and postnatally, and the medical history of other family members. We will examine the quality and quantity of foetal movements and its association with the development of OSA. The occurrence of sleep and breathing disorders in the infants will be correlated with the foetal behaviour and, the prenatal and postnatal factors.Read moreRead less
Antibodies Against Erythrocyte Invasion Ligands Of Plasmodium Falciparum And Protection From Malaria
Funder
National Health and Medical Research Council
Funding Amount
$358,184.00
Summary
Malaria is a leading cause of childhood death globally. Malaria parasites infect red blood cells and multiply inside them, resulting in severe illness if untreated. Currently there is no vaccine available and effective treatments are limited. In studies of children in Africa and PNG, we aim to identify immune responses that block infection and growth of malaria in the blood. With this knowledge, vaccines can be designed that target malaria to prevent serious illness and death.
Modification Of Dendritic Cell Function And Priming Of Protective Immunity By Malaria Blood-stage Parasites
Funder
National Health and Medical Research Council
Funding Amount
$316,500.00
Summary
Approximately 2 billion individuals live in areas where malaria is a risk. Children and naive individuals who get infected for the first time, usually travellers, are most at risk of dying from a Plasmodium falciparum infection, with an estimated 2 million children under 3 years of age killed each year. Surviving adults living in malarial areas have partial immunity after a series of infections. It is unclear how this protective immunity, particularly cellular immunity is acquired, and also uncl ....Approximately 2 billion individuals live in areas where malaria is a risk. Children and naive individuals who get infected for the first time, usually travellers, are most at risk of dying from a Plasmodium falciparum infection, with an estimated 2 million children under 3 years of age killed each year. Surviving adults living in malarial areas have partial immunity after a series of infections. It is unclear how this protective immunity, particularly cellular immunity is acquired, and also unclear why it takes so long to develop. Recent advances in immunology have indicated that Dendritic Cells (DCs) are necesssary to induce effectively cellular immunity and prime memory responses. DCs take up foreign proteins and show them to T cells resulting in their activation. T cells are critical for the establishment of long-term protective immunity to malaria. However, it has not been known if DC can take up malaria parasites or malaria infected red-blood cells and process them to activate protective T cell responses. Our preliminary data shows that both human and mouse DC can take up parasitised red-cells, but that the interaction of parasite derived proteins on the surface of the red cell with DC receptors causes a defect in DC maturation. This defect may prevent effective priming of T cells during natural malaria infection, contributing to the poor development of immunity in malaria endemic areas. Given these novel fundamental findings, it is now important to elucidate: 1) The nature of the DC defect induced by the parasites 2) Assess whether this is a common feature of all Plasmodia, or whether it may relate to strain virulence 3) Determine the nature and extent of the malaria specific response induced by the defective DC. Understanding how parasites may be able to sabotage a critical inducing component of the immune system has wide implications for the use of any immuno-therapies in malaria endemic regions.Read moreRead less
Children Of Parents With Mental Illness: A Population-based Study
Funder
National Health and Medical Research Council
Funding Amount
$774,715.00
Summary
Schizophrenia, bipolar disorder and major depression account for about 16% of the global burden of disease, according to estimates by the World Health Organization and the World Bank. These disorders tend to run a chronic or recurrent course, with devastating impact on sufferers and their families. We know today that part of their causes are genetic and may be transmitted to the next generation. However, another part of the causation is likely to be environmental, involving maternal pregnancy co ....Schizophrenia, bipolar disorder and major depression account for about 16% of the global burden of disease, according to estimates by the World Health Organization and the World Bank. These disorders tend to run a chronic or recurrent course, with devastating impact on sufferers and their families. We know today that part of their causes are genetic and may be transmitted to the next generation. However, another part of the causation is likely to be environmental, involving maternal pregnancy complications, as well as psychosocial adversity and stressful events impacting children who happen to carry a genetic susceptibility to such disorders. To disentangle and understand better such effects, our research is focusing on families where genetic risk to the offspring is present, due to a mother suffering from one of these disorders. By linking data available on population databases in WA, we aim to follow up the childhood development and young adult health outcomes of all children born to women with schizophrenia, bipolar disorder or depression. Few studies of this kind have been done worldwide, and we expect that the WA study will answer many unresolved questions, leading to preventative and treatment interventions that would reduce adverse outcomes and improve the quality of life of families at risk.Read moreRead less
Identifying The Targets Of Protective Immunity To Malaria In Pregnancy
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
Malaria in pregnancy is a major cause of disease across many countries. Pregnant women have a high risk of malaria, and large numbers of malaria parasites accumulate in the placenta, which may lead to infant or maternal death. Malaria parasites infect the placenta by producing proteins that enable them to stick to the placenta. These malaria strains causing placental infection generally do not cause disease in non-pregnant individuals. Antibodies to the parasite proteins are produced in response ....Malaria in pregnancy is a major cause of disease across many countries. Pregnant women have a high risk of malaria, and large numbers of malaria parasites accumulate in the placenta, which may lead to infant or maternal death. Malaria parasites infect the placenta by producing proteins that enable them to stick to the placenta. These malaria strains causing placental infection generally do not cause disease in non-pregnant individuals. Antibodies to the parasite proteins are produced in response to placental infection, which may help control the infection and protect against further malaria in pregnancy. However, placental malaria parasites are able to vary the proteins they produce to avoid immune responses. In this project, we will study the parasite strains that cause malaria in pregnancy and the development of antibodies that protect pregnant women against malaria and its complications. We aim to identify the genes and proteins that parasites use to stick to the placenta, and determine how much variation occurs in these proteins. We will also specifically examine the role of one particular candidate gene called var2csa, and its protein, as this has been recently been associated with pregnancy malaria. We will examine how antibodies develop that recognise different proteins and different forms of malaria parasites, and determine the type of antibodies that protect pregnant women taking part in a longitudinal study of malaria in pregnancy in Malawi, Africa. We will also examine how antimalarial drugs taken in pregnancy influence the development of protective antibodies. Through these studies we aim to understand how the immune system combats malaria in pregnancy. This will be important for developing new methods for preventing or treating malaria in pregnancy, and improving child and maternal health.Read moreRead less
PROTECTING THE PRETERM FETAL BRAIN FROM HYPOXIA AND INFECTION: A HEALTHY START TO LIFE.
Funder
National Health and Medical Research Council
Funding Amount
$495,750.00
Summary
Brain damage during fetal life is a significant cause of later neurological problems such as cerebral palsy. Recent studies have shown that brain injury detected in infants is usually caused by adverse conditions within the uterus prior to labour, but the exact causes are poorly understood. It is also apparent that babies born prematurely are at increased risk of suffering serious brain damage. In recent years it has become evident that infections in the mother may be linked to both premature bi ....Brain damage during fetal life is a significant cause of later neurological problems such as cerebral palsy. Recent studies have shown that brain injury detected in infants is usually caused by adverse conditions within the uterus prior to labour, but the exact causes are poorly understood. It is also apparent that babies born prematurely are at increased risk of suffering serious brain damage. In recent years it has become evident that infections in the mother may be linked to both premature birth and brain damage. It has been proposed that certain chemicals (cytokines), which are released during an infection, can cross the placenta to the fetus causing inflammatory changes that lead to brain damage. We have shown that an inflammatory inducing chemical (bacterial endotoxin) administered to immature fetal sheep induces brain damage similar to that seen in cerebral palsy. This provides an excellent model for testing agents that are known to block the action of cytokines and other markers of inflammation; currently there is no effective strategy for the treatment or prevention of hypoxia and inflammatory induced injury of the brain partly due to our ignorance about how and when the damage is occurring. We will test the effects of two chemicals; N-acetyl cysteine, which is known to block the generation of inflammatory cytokines, and the naturally occurring glycoprotein erythropoietin, which prevents death of neurons (apoptosis). We hope that by blocking these pathways we may be able to prevent brain injury from occurring when the immature fetus is exposed to an infection during gestation. We expect that this project will provide important novel information that helps us to understand how infection in the mother can cause brain injury in the fetus and provide a new approach for strategies to prevent or treat brain injury.Read moreRead less
Defining The Targets And Function Of Antibodies That Protect Against Malaria In Pregnancy
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Malaria during pregnancy is a major cause of maternal and infant morbidity and mortality globally. In this project we aim to define the targets of antibodies that protect against malaria in pregnancy and understand the importance of antibody function, determine the extent of antigenic diversity, and identify epitopes of protective antibodies. Results will provide critical knowledge on the development of immunity to malaria in pregnancy that will guide vaccine development.