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Suppression Of NADPH Oxidase-derived Oxidative Stress By Anti-sense Probes And HDL In Human Vascular Endothelium
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
In Australia, coronary heart disease (CHD) causing heart attacks remains the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, is an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the key cells that form the lining of all arteries, known as the vascular endothelium. By using novel DNA-type molecules (known as anti-sense) develo ....In Australia, coronary heart disease (CHD) causing heart attacks remains the largest cause of death, claiming a staggering 28,000 lives a year. Oxidative stress, resulting from increased production of oxygen free radicals in arteries, is an important cause of CHD, heart attacks and strokes. We seek to understand how such oxyradicals are produced in the key cells that form the lining of all arteries, known as the vascular endothelium. By using novel DNA-type molecules (known as anti-sense) developed in our laboratory, which block a particular gene causing oxidative stress, we will determine whether this gene is responsible for the formation of oxyradicals in human and mouse cells grown in culture. In addition, we will explore whether this gene is turned on by factors known to be involved in CHD. Finally, we will also investigate whether the good cholesterol known as HDL can act to prevent oxidative stress in human cells, as we discovered it appears to do in living arteries in vivo. If we find it has the same protective effect in endothelium, we will determine how it does this, and which component proteins of the HDL particle are important. This might suggest new treatments to prevent acute events leading to heart attack and stroke, and possibly new applications where damage appears to result from acute oxidative stress, such as in the brain soon after a stroke has occurred. We also have a plan to develop antisense drugs that will target the important gene specifically in the affected endothelium. In addition, we have other specific new drugs that will block this system in arteries. Simultaneously we will be testing the role of this gene in mouse and rabbit models of artery disease, for both our types of drugs might provide valuable new therapeutic agents to target the underlying cause of CHD and not just its symptoms as current drugs do.Read moreRead less
Early Intervention For Anxiety And Phobic Disorders In Young Children With Intellectual Disability
Funder
National Health and Medical Research Council
Funding Amount
$305,674.00
Summary
Children with intellectual disability (ID) are 2-3 times more likely to have behavioural and emotional disturbance, including anxiety and fears, than children of normal intellectual ability. Anxiety problems are a source of distress for the child, impair their ability to learn and are a cause of family burden and community cost. Therefore, effective interventions are urgently required. Research with non-disabled children has demonstrated the effectiveness of teaching parents to manage their chil ....Children with intellectual disability (ID) are 2-3 times more likely to have behavioural and emotional disturbance, including anxiety and fears, than children of normal intellectual ability. Anxiety problems are a source of distress for the child, impair their ability to learn and are a cause of family burden and community cost. Therefore, effective interventions are urgently required. Research with non-disabled children has demonstrated the effectiveness of teaching parents to manage their child's anxiety, however the effectiveness of this approach in children with ID has not yet been established. This project aims to compare the relative effectiveness of two intervention conditions compared to a waiting list group, for highly anxious children aged 4-7 years with ID. One intervention will teach parents to help their child deal with anxiety problems, and develop skills to overcome their own associated emotional upset and family and social problems. The other intervention will provide non-directive counselling and support to help the parents understand the nature and causes of ID, associated anxiety problems in the child, and parent and family stress. The long term outcome of these two interventions will be assessed by following the children and their families for two years. A manual of each treatment is produced. This project aims to provide evidence for a relatively inexpensive, feasible and effective early intervention program for young children with ID at risk for developing anxiety problems that can be easily taught to professionals and is acceptable to parents. Widespread use of this intervention has the potential to reduce the added burden and cost to families and the community of persistent severe anxiety in young people with ID.Read moreRead less
Circulating Low -molecular Weight AGEs In The Development And Progression Of Diabetic Complications
Funder
National Health and Medical Research Council
Funding Amount
$297,523.00
Summary
High levels of sugars seen in patients with diabetes leads to damage of many organs including the heart, the eyes and the kidneys. These high sugars cause damage through a number of mechanisms, one being the formation of advanced glycation end products or AGEs, formed by the irreversible reaction between proteins and glucose. This reaction leads to a change in the shape and function of AGE-modified molecules that progressively contributes to organ damage. AGEs also bind and activate specific rec ....High levels of sugars seen in patients with diabetes leads to damage of many organs including the heart, the eyes and the kidneys. These high sugars cause damage through a number of mechanisms, one being the formation of advanced glycation end products or AGEs, formed by the irreversible reaction between proteins and glucose. This reaction leads to a change in the shape and function of AGE-modified molecules that progressively contributes to organ damage. AGEs also bind and activate specific receptors that promote the damage and scarring of tissue. Where the glucose concentration is high, AGEs accumulate much more quickly. This is one reason why patients with good sugar control do better than those who are unable to control their blood sugars. The importance of this AGE pathway is illustrated by the fact that blocking the formation of AGEs is able to prevent kidney damage in animals with diabetes. In addition, exposure to AGEs can cause diabetes-like changes in the absence of high sugars. Our laboratory is a world leader in the study of the advanced glycation and methods blocking this process. The research proposed will investigate circulating levels of AGEs in experimental animals and patients with diabetes, and correlate them with the development and progression of complications of diabetesRead moreRead less
Population Prevalence And Environmental-genetic Predictors Of Food Allergy In An Infant Cohort
Funder
National Health and Medical Research Council
Funding Amount
$551,642.00
Summary
This study will measure which children are at greatest risk of food allergy. We plan to recruit 5000 children to test for food allergies, as well as asking a range of questions on different lifestyle factors such as diet and history of allergies . If positive, participants will be invited to a hospital clinic for tests and treatment. This will allow us to describe the epidemiology of food allergy, and assist the development of better services for those with food allergy in the community.
A Population-based Family Study Of Filaggrin Mutations And Allergic Disease Risk In Australia
Funder
National Health and Medical Research Council
Funding Amount
$308,584.00
Summary
It is biologically plausible that the association of known environmental risk factors for asthma may be different for genetically susceptible individuals. Few studies have examined the interaction between genetic and environmental factors. that have not considered genetic susceptibility are estimating an average risk of asthma across all genotypes in the population which may not be relevant for a particular sub-group.
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
The Clinical Value Of Serology And Molecular Tests For Diagnosing Invasive Aspergillosis In At-risk Hematology Patients
Funder
National Health and Medical Research Council
Funding Amount
$1,095,500.00
Summary
Aspergillus is a fungus found in soil, on farms and on construction sites. In those whose immune system is impaired it causes severe infection. The people who are particularly at high-risk of Aspergillus infection (called Invasive Aspergillosis) are those with acute leukaemia on chemotherapy or post bone marrow transplantation. Currently 15% of those at high-risk get Invasive Aspergillosis and 58-93% of those infected die. The main reason for this high death rate is that our current diagnostic t ....Aspergillus is a fungus found in soil, on farms and on construction sites. In those whose immune system is impaired it causes severe infection. The people who are particularly at high-risk of Aspergillus infection (called Invasive Aspergillosis) are those with acute leukaemia on chemotherapy or post bone marrow transplantation. Currently 15% of those at high-risk get Invasive Aspergillosis and 58-93% of those infected die. The main reason for this high death rate is that our current diagnostic tests are not good at detecting infection or often only detect the infection at advanced stages when treatment is ineffective. Because of the limitations of current diagnostic tests the current practice is to give empiric antifungal therapy (EAFT) early to treat Invasive Aspergillosis. However studies have demonstrated that this therapy has only resulted in a minor reduction in the mortality rates and it causes significant drug toxicity. It is a suboptimal treatment modality. New tests have been developed to diagnose Invasive Aspergillosis. These tests are for the detection of an Aspergillus protein in blood and for the detection of Aspergillus DNA in the blood. Available data suggests that these new tests are sensitive in the detection of Invasive Aspergillosis. Also other studies suggest that these new tests make an early diagnosis and seem to be able to monitor responses to treatment. However no study has been performed to date which demonstrates that the use of these tests can impact on important patient outcomes. This trial is designed to determine whether the use of the new tests to guide therapy will help improve treatment of Invasive Aspergillosis, reduce drug toxicity and reduce the death rate in the high-risk patients as compared with the current standard method of diagnosis and treatment with EAFT. If the trial is successful then this represents a significant advancement in the treatment and survival of leukaemic and bone marrow transplantation patients.Read moreRead less
An Integrated Approach For The Efffective Adoptive Immunotherapy Of Cancer
Funder
National Health and Medical Research Council
Funding Amount
$468,119.00
Summary
Killer T lymphocytes can penetrate tumors and their transfer into cancer patients has demonstrated some encouraging results, but this form of immunotherapy remain ineffective in most cancer patients. We propose to improve the tumor trafficking and anti-tumor activities of killer cells by genetically engineering them with proteins that will enable them to recognise and destroy cancer cells. The outcomes of this project will validate this novel approach for treatment of cancer patients.