Prenatal Alcohol Exposure: A Molecular Mechanism For Memory Deficits Involving The Zinc-binding Protein, Metallothionein
Funder
National Health and Medical Research Council
Funding Amount
$277,645.00
Summary
Damage to the developing brain is the major social and economic consequence of prenatal alcohol exposure but it is unclear the mechanism by which this occurs. This study will assess whether the maternal zinc-binding protein, metallothionein, causes: 1) alcohol-related cognitive deficits, 2) changes in the expression of alcohol-sensitive cognitive genes. We will further assess whether dietary zinc supplementation throughout pregnancy can prevent alcohol-related anomalies in neurodevelopment.
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
INVESTIGATING THE VALIDITY OF PRENATAL INSULTS AS RISK FACTORS FOR SCHIZOPHRENIA.
Funder
National Health and Medical Research Council
Funding Amount
$201,100.00
Summary
Schizophrenia is one of the most devastating of human mental disorders affecting about 1% of the population. The cause of this disorder is not known but it seems certain that it will involve genetic and environmental factors. An adverse environmental factor could be a reduced supply of oxygen and nutrients to a baby during pregnancy. In guinea pigs we aim to investigate whether disruption to the normal supply of oxygen and nutrients to the fetus disrupts the normal fine structure and chemical ma ....Schizophrenia is one of the most devastating of human mental disorders affecting about 1% of the population. The cause of this disorder is not known but it seems certain that it will involve genetic and environmental factors. An adverse environmental factor could be a reduced supply of oxygen and nutrients to a baby during pregnancy. In guinea pigs we aim to investigate whether disruption to the normal supply of oxygen and nutrients to the fetus disrupts the normal fine structure and chemical make up of the brain and gives rise to long-lasting structural and neurochemical changes in adolescent animals, which resemble changes found in the brains of patients with schizophrenia. We will also assess whether behavioural responses of compromised animals are altered in tests that parallel disturbances seen in patients with schizophrenia. Such abnormal brain development could create an underlying vulnerability in the brain, predisposing individuals with risk factors such as genetic inheritance to develop the symptoms of schizophrenia in later life perhaps only after the complete formation of nerve pathways involved in higher brain functioning. If guinea pigs that have been subjected to low oxygen levels during pregnancy show sustained changes in the structure and neurochemistry in regions of the brain that are altered in patients with schizophrenia it would suggest that these long lasting disturbances could result from problems during pregnancy. Thus, this would support the idea that abnormal brain development during pregnancy is one of the underlying causes of schizophrenia.Read moreRead less
The Impact Of Severe Asthma During Pregnancy On Placental Function And Fetal Hypothalamic-pituitary-adrenal Function
Funder
National Health and Medical Research Council
Funding Amount
$209,242.00
Summary
This study will examine whether the glucocorticoids administered for the control of severe asthma during pregnancy affects placental and fetal function. It is known that severe asthma during pregnancy is associated with low birth weight babies but the events that cause reduced growth of the baby are unknown. However in both animal and human pregnancies, increased exposure of the baby to glucocorticoids from the mother causes growth restriction of the baby. Therefore we propose that the increased ....This study will examine whether the glucocorticoids administered for the control of severe asthma during pregnancy affects placental and fetal function. It is known that severe asthma during pregnancy is associated with low birth weight babies but the events that cause reduced growth of the baby are unknown. However in both animal and human pregnancies, increased exposure of the baby to glucocorticoids from the mother causes growth restriction of the baby. Therefore we propose that the increased intake of glucocorticoids for the treatment of asthma during pregnancy changes how the placenta functions and allows the fetus to be exposed to maternal glucocorticoids causing changes in fetal development. We will examine placental blood flow and measure some placental enzymes that may be involved in the control of blood flow in placentas collected from women with mild, moderate and severe asthma and compare them to non-asthmatic women. We will look at placental blood flow in utero using Doppler ultrasound and also in vitro after the placenta is delivered. We want to see if the fetus is affected by increased intake of glucocorticoids by the mother by measuring a hormone estriol, which originates from the fetus. We will measure estriol throughout pregnancy as it can easily be detected in the mothers' urine. These studies will tell us if glucocorticoid intake for the treatment of asthma can exert effects on the placenta and baby during pregnancy. These studies will make a significant contribution both scientifically and clinically. At a scientific level we will be able to examine how increased maternal glucocorticoid intake during pregnancy affects placental mechanisms and whether these changes affect the fetus and clinically the outcome of this study will allow us to optimize asthma therapy during pregnancy so that we can improve the outcome for the baby.Read moreRead less
FETAL BRAIN INJURY RESULTING FROM INTRAUTERINE INFECTION: LONG TERM CONSEQUENCES AND THE POTENTIAL FOR INTERVENTION
Funder
National Health and Medical Research Council
Funding Amount
$452,640.00
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. Unfortunately, at present, it is not possible to prevent or effectively treat brain damage in the fetu ....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. Unfortunately, at present, it is not possible to prevent or effectively treat brain damage in the fetus or newborn, partly due to ignorance about how and when the damage is occurring. 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 the certain chemicals (cytokines) which are released during an infection can across the placenta to the fetus, causing inflammatory changes that lead to brain damage. However, although associations have been shown in studies of women, there is little evidence that infections actually cause brain damage in the fetus. This project will define the effects of an inflammation inducing chemical (bacterial endotoxin) on the fetal brain and the pattern of inflammation it sets up in the fetus. We will also examine the effects of brain damage caused by endotoxin in the newborn lamb, and relate this to alterations in behaviour. Once we have defined the effects of endotoxin on brain structure, we will test the effects of chemicals that are known to block the actions of inflammatory cytokines. We hope that by blocking the chemical pathway that leads to the production of harmful cytokines we may be able to prevent brain injury from occurring when the fetus is exposed to an infection in the mother. It is expected that this project will provide important information that helps us to understand how infection in the mother can cause brain injury in the fetus. This information is vital if strategies to prevent or treat brain injury are to be developed.Read moreRead less
Neuroscience On Barriers In Development (NEUROBID)
Funder
National Health and Medical Research Council
Funding Amount
$600,927.00
Summary
The program aims to understand normal and disturbed brain barrier function in development to devise ways of preventing or ameliorating neurological conditions in infants or adult neurological disorders with developmental origins. Unique features of transport mechanisms across brain barriers will be used to design novel methods of targeting therapeutic macromolecular and cellular agents to the brain barriers and transporting them into brain for treatment of neurological diseases in young and old.
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
Neonatal Vitamin D Status And Risk Of Schizophrenia: A Study Using Danish Dried Bloods Spots
Funder
National Health and Medical Research Council
Funding Amount
$164,980.00
Summary
There is increasing evidence that low levels of vitamin D (i.e. the 'sunshine hormone') during early development can alter brain development. In particular, it has been proposed that low vitamin D during development (e.g. prenatal and in early life), increases the risk of developing schizophrenia during adulthood. A previous study based on stored third trimester blood samples from US women suggested that very low levels of maternal vitamin D may be associated with an increased risk of schizophre ....There is increasing evidence that low levels of vitamin D (i.e. the 'sunshine hormone') during early development can alter brain development. In particular, it has been proposed that low vitamin D during development (e.g. prenatal and in early life), increases the risk of developing schizophrenia during adulthood. A previous study based on stored third trimester blood samples from US women suggested that very low levels of maternal vitamin D may be associated with an increased risk of schizophrenia in the offspring. We have the opportunity to explore this hypothesis using a large, well-described Danish 'bio-bank'. Since 1981, blood samples from newborn babies have been kept by a central agency in Denmark. In collaboration with senior Danish medical researchers, 900 blood samples of babies who have subsequently developed schizophrenia and 1800 from matched healthy individuals have been identified. We will measure vitamin D levels in these blood samples. We predict that babies with low levels of vitamin D will have an increased risk of developing schizophrenia. If low prenatal vitamin D does increase the risk of schizophrenia, this finding will have important implications from a public health perspective. Just as the number of infants affected by spina bifida has been reduced by adding folate supplements to foods, optimizing maternal vitamin D levels may lead to a reduction in the incidence of schizophrenia.Read moreRead less
Molecular And Cellular Mechanisms Of Axon Guidance In The Vertebrate Nervous System
Funder
National Health and Medical Research Council
Funding Amount
$330,735.00
Summary
There are, at least, two major obstacles that have to be overcome in the design of therapies to assist the repair of injured brain tissue. First, the nerve cells that are damaged have to be encouraged to regrow - typically this regrowth is inhibited in the brain; and second, this regrowth has to be directed so that the correct connections are re-established. This project will begin to unravel some of the mechanisms that nerve cells use to wire up together during development. This information can ....There are, at least, two major obstacles that have to be overcome in the design of therapies to assist the repair of injured brain tissue. First, the nerve cells that are damaged have to be encouraged to regrow - typically this regrowth is inhibited in the brain; and second, this regrowth has to be directed so that the correct connections are re-established. This project will begin to unravel some of the mechanisms that nerve cells use to wire up together during development. This information can be used to assist in trying to modulate and facilitate directed regrowth following injury.Read moreRead less
Personalising The Delivery Of E-mental Health Interventions For Eating Disorders
Funder
National Health and Medical Research Council
Funding Amount
$632,429.00
Summary
This Investigator Grant aims to evaluate the efficacy and cost-effectiveness of an eHealth prevention and treatment program using a stepped-care approach. Findings are expected to show that eating disorders can be effectively and efficiently treated and prevented through low intensity, cheap, and widely available digital interventions, and by doing so it will directly address the unmet needs of people with or at risk for an eating disorder in a practical, scalable, and cost-effective manner.