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Treatment Of Cerebral Palsy - An Experimental Approach
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Cerebral palsy is characterised by disordered movement evident early in life leading to lifelong disability. The motor disorder arises from an abnormality within the white-matter of the brain that is non-progressive and is identifiable soon after birth. In humans and experimental models of fetal infection there is an increase in markers of inflammation. We will use induce ovine fetal infection and white matter injury to examine if anti-inflammatory treatments can prevent fetal brain damage.
Intrauterine Ureaplasma Infection During Pregnancy: Fetal Effects And Characteristics Of Ureaplasma Pathogenicity.
Funder
National Health and Medical Research Council
Funding Amount
$527,097.00
Summary
Ureaplasmas are microorganisms that are commonly found in the urinary tracts of men and women, without any apparent adverse effects; but their presence in amniotic fluid during pregnancy is associated with preterm birth and other adverse pregnancy outcomes. The effects that ureaplasmas in the amniotic fluid have on the developing baby before birth are likely to result in illness after birth, but the range of potential effects is unknown. We also know very little about how ureaplasmas themselves ....Ureaplasmas are microorganisms that are commonly found in the urinary tracts of men and women, without any apparent adverse effects; but their presence in amniotic fluid during pregnancy is associated with preterm birth and other adverse pregnancy outcomes. The effects that ureaplasmas in the amniotic fluid have on the developing baby before birth are likely to result in illness after birth, but the range of potential effects is unknown. We also know very little about how ureaplasmas themselves manage to infect the fetus and other tissues within the pregnant uterus. Our studies are designed to identify the effects that ureaplasmas in amniotic fluid have on the developing fetus and how common treatments during pregnancy impact on those effects. We will also study ureaplasmas to see what it is about them that allows them to affect the fetus and other uterine tissues. We expect that our studies will lead to better diagnosis and treatment of amniotic ureaplasma infection during pregnancy, and will allow us to better care for babies born after exposure to ureaplasmas before birth.Read moreRead less
Blood-brain Barrier And White Matter Damage In The Immature Rat Brain Following Systemic Inflammation
Funder
National Health and Medical Research Council
Funding Amount
$353,173.00
Summary
Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infecti ....Clinical obstetric and paediatric studies have identified an association between intrauterine infection occurring around two thirds of the way through pregnancy, premature birth and a specific form of damage to the brain of the newborn. This damage mainly affects white matter tracts. These tracts are aggregations of nerve fibres that make the connections between different parts of the brain and may result in cerebral palsy or other neurological disorders. The association between maternal infection and brain damage, one form of which is cerebral palsy, is well established from clinical epidemiological studies, but the biological mechanism of this link is unknown. The CIs' group has recently shown that the condition can be reproduced in neonatal rats at a stage of brain development in the rat that is equivalent to the critical time in human brain development when infection may be associated with brain damage. The CIs' group has shown that an induced inflammatory state similar to a bacterial infection, results in damage to blood vessels in the white matter and is associated with changes in white matter, as occurs in affected babies. The purpose of this study is to understand the nature of the damage to white matter blood vessels and the mechanisms by which materials in blood, which in the normal brain do not pass from the blood to the brain across the blood-brain barrier, are able to do so via the inflammation damaged blood vessels. The study also aims to show whether it is components of the blood entering the brain via the damaged blood vessels that are responsible for the damage to white matter in the immature brain. The outcome should lead to development of ways to improve clinical care of women who acquire infections during pregnancy.Read moreRead less
The Fetal Response To Infection, With Particular Reference To Alterations Of Tryptophan Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$410,616.00
Summary
Infection in pregnancy has long been known to be associated with a high risk for brain damage in the baby. There is now good evidence that the brain can be damaged before birth, and in other babies where the brain is damaged after birth there is reason to say that these infants were factors associated with the pregnancy that rendered them vulnerable to risk factors postnatally. Very little is known about the effects of infection on the fetus. Some recent work has shown that substances released f ....Infection in pregnancy has long been known to be associated with a high risk for brain damage in the baby. There is now good evidence that the brain can be damaged before birth, and in other babies where the brain is damaged after birth there is reason to say that these infants were factors associated with the pregnancy that rendered them vulnerable to risk factors postnatally. Very little is known about the effects of infection on the fetus. Some recent work has shown that substances released from bacteria induce cells in the uterus and placenta to produce inflammatory chemicals that can damage the brain. In this project we propose the following model: 1), infection causes the release of substances from the uterus and placenta that disrupt the blood-brain barrier in the fetal brain; and, 2), infection alters the metabolism of the essential amino acid tryptophan in the fetus, causing greater production of metabolites that have toxic effects on the developing brain. We have preliminary evidence to support these two proposals. If the idea is proven correct, it should be possible to administer simple analogues of tryptophan to prevent the toxic metabolites of this amino acid from increasing in the fetus when either the mother or the uterus becomes infected. Because these substances can be given by mouth, this would allow a simple treatment to be developed for women at risk of infection, or who are already infected. This would be particularly useful wherever medical services and resources are limited, as for under-priviledged groups and in Third World countries.Read moreRead less
A Genomic Basis For Cerebral Palsy - Studies On A Large Australian Cohort
Funder
National Health and Medical Research Council
Funding Amount
$518,305.00
Summary
Cerebral Palsy (CP) is the commonest neurological disability in children, affecting 1 in every 500 children. This research will investigate genetic causes of CP by testing families with and without CP for a range of genetic alterations that change fetal protection to inflammation with resultant brain damage and CP. Research in to the causes of CP will allow prevention strategies to be developed, to ultimately reduce social and financial costs of CP for the patient, their family and the community ....Cerebral Palsy (CP) is the commonest neurological disability in children, affecting 1 in every 500 children. This research will investigate genetic causes of CP by testing families with and without CP for a range of genetic alterations that change fetal protection to inflammation with resultant brain damage and CP. Research in to the causes of CP will allow prevention strategies to be developed, to ultimately reduce social and financial costs of CP for the patient, their family and the community.Read moreRead less
Impact Of Chronic Intrauterine Inflammation On Neurodevelopmental & Physiological Responses To Fetal Hypoxia.
Funder
National Health and Medical Research Council
Funding Amount
$280,750.00
Summary
Careful examination of records from hundreds of pregnancies has indicated that low-grade infection or inflammation within the uterus during pregnancy is associated with an increase in the likelihood that the newborn baby will suffer from cerebral palsy. This strong association suggests that inflammation during pregnancy can cause damage to the developing baby's brain. Similar studies have also identified an association betwen events that result in a lack of oxygen supply to the developing brain ....Careful examination of records from hundreds of pregnancies has indicated that low-grade infection or inflammation within the uterus during pregnancy is associated with an increase in the likelihood that the newborn baby will suffer from cerebral palsy. This strong association suggests that inflammation during pregnancy can cause damage to the developing baby's brain. Similar studies have also identified an association betwen events that result in a lack of oxygen supply to the developing brain and cerebral palsy. However the studies that have identified these associations are incapable of determining the mechanisms by which these factors affect brain development. Even though inflammation during pregnancy is common, and is often associated with diseases after birth, experimental studies of the effects of this type of inflammation on the wellbeing of the unborn baby have not been performed. Our research group has developed a unique experimental model, using sheep, which is particularly suitable for determining how inflammation and a lack of oxygen may affect the unborn baby and cause brain damage. By continuously giving a sterile bacterial cell wall preparation (endotoxin) into the amniotic fluid of pregnant sheep we can cause prolonged inflammation with characteristics that are similar to those that accompany inflammation during human pregnancy but different to other models of inflammation within the uterus. We intend to use our model to determine how prolonged inflammation and a lack of oxygen affect the well-being of the developing lamb before birth and how these factors affect brain development. Our proposed study will provide valuable information about how inflammation and a lack of oxygen interact to affect brain development. We expect that when inflammation is present the fetus becomes more vulnerable to the effects of a lack of oxygen, resulting in more severe brain damage occuring than when either factor is experienced alone.Read moreRead less
COMPARATIVE ANTI-BACTERIAL IMMUNITY IN THE URINARY TRACT: DOES ONE SIZE FIT ALL?
Funder
National Health and Medical Research Council
Funding Amount
$376,781.00
Summary
Urinary tract infections (UTI), which start as a bladder infection and often evolve to encompass the kidneys, are among the most common infectious diseases of humans. It is estimated that 40 to 50% of adult healthy women have experienced at least one UTI episode in their lifetime. Bacteria cause most UTI and this study will focus on how these bacteria survive in the urinary tract and will provide key insight into the ways in which human immune responses develop to counteract these bacteria.
Chronic Bacterial Infection And The Generation Of T Cell Memory: Implication For Vaccination Against Tuberculosis
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
Two million people die from tuberculosis (TB) each year. The immune system is unable to eradicate the TB bacterium, and the type of immune response needed to protect against the disease is poorly understood. We will use animal models of TB infection and sophisticated immunological techniques to decipher how the TB bacterium interacts with the immune sytem and causes disease. We will also develop new TB vaccines that aim to boost the immune response in the lung, the main site of TB infection.
Bacterial Outer Membrane Vesicles As Immunomodulatory Agents In Helicobacter Pylori Infection
Funder
National Health and Medical Research Council
Funding Amount
$306,510.00
Summary
Chronic inflammation of the stomach is a hallmark of Helicobacter pylori infection, and is a precursor to peptic ulcer disease and cancer. Like many other bacteria, H. pylori sheds spherical blebs from its surface. These blebs bind to stomach cells in vitro and have been found in stomach biopsies of H. pylori-infected subjects. The aims of the work are to investigate the mechanisms whereby H. pylori blebs enter and disseminate within host cells, and how this may contribute to inflammation.
Manipulating Immunity To Mycobacterium Tuberculosis With Novel Vaccines And Immunotherapeutics
Funder
National Health and Medical Research Council
Funding Amount
$524,770.00
Summary
Tuberculosis (TB) is an enormous world health problem with 2 million deaths per year and an estimated one third of the world s population infected with the TB bacterium. People who become infected with the bacterium and cannot clear the infection are at great risk of developing TB later in life. Control of TB is confronted with two major problems. First, the only vaccine available for TB, known as BCG, is not very effective at preventing the disease. We do not know why BCG is not an effective va ....Tuberculosis (TB) is an enormous world health problem with 2 million deaths per year and an estimated one third of the world s population infected with the TB bacterium. People who become infected with the bacterium and cannot clear the infection are at great risk of developing TB later in life. Control of TB is confronted with two major problems. First, the only vaccine available for TB, known as BCG, is not very effective at preventing the disease. We do not know why BCG is not an effective vaccine and the type of immune response required to achieve optimal protection against TB is not fully understood. Second, the drugs currently used to treat TB are expensive, treatment times are long and drug resistance is increasing at an alarming rate. Therefore there is an urgent need to develop new vaccines and therapies against TB. We propose to use animal models of TB infection and sophisticated immunological techniques to compare immune responses generated by TB, BCG and new generation vaccines developed in our laboratory. This will allow us to identify the key features of a vaccine that results in effective, long-lasting protection against TB infection. Novel strategies to increase the immune response in the lung, the main site of TB infection, will also be examined. This will involve pulmonary delivery of molecules that increase the number and effectiveness of lung antigen presenting cells, which are necessary to drive the right type of immune response to eradicate the TB bacterium. Increasing lung immunity will be used to either boost the effect of the BCG vaccine, or as a therapy to kill the bacterium in those already infected. This is an internationally competitive project and our team is at the forefront of this research effort. The development of new vaccines to prevent TB or new strategies to treat established TB infection would be a major medical breakthrough and a represent a significant achievement for Australian health and medical research.Read moreRead less