The Role Of Melanoma Tumour Antigen P97 (Melanotransferrin) In Melanoma Tumourigenesis.
Funder
National Health and Medical Research Council
Funding Amount
$563,242.00
Summary
The Role of Melanoma Tumour Antigen p97 (Melanotransferrin) in Melanoma Tumourigenesis Melanotransferrin (MTf) is a homologue of the iron transport protein, transferrin, and was one of the first well characterised melanoma tumour antigens. Our published studies have shown that MTf plays an important role in melanoma tumourigenesis in vivo. In this proposal, we will assess if it is associated with melanoma progression in patient samples and examine its role in melanoma growth and metastasis.
Therapeutic Implications Of A Molecular Link Between Survivin And Telomerase Reverse Transcriptase
Funder
National Health and Medical Research Council
Funding Amount
$547,970.00
Summary
A unifying feature of all types of cancer cells is that they are immortal. Our investigations will build upon our recent results that showed the gene survivin is involved in cancer cell immortalisation. We will characterise a molecular link between survivin and the enzyme telomerase, which is central to cancer cell immortality. Furthermore, we will demonstrate the therapeutic potential of turning off both survivin and telomerase as a novel approach to halting the growth of cancer cells.
How Do Thick Airway Walls Affect Airway Hyperresponsiveness In Asthma?
Funder
National Health and Medical Research Council
Funding Amount
$382,538.00
Summary
Asthmatic airways narrow too easily, a characteristic called airway hyperresponsiveness (AHR). To understand the cause of asthma we need to understand the cause of AHR. Thickened airway walls could amplify airway narrowing and increase AHR. However, thick airway walls are also stiff, and stiff walls could reduce narrowing and AHR. This project will examine the relationships between AHR and airway wall thickness and stiffness during and after treatment that reduces airway wall thickness.
Does Caffeine Affect The Development Of The Very Immature Brain: Dose Response Relationship?
Funder
National Health and Medical Research Council
Funding Amount
$668,386.00
Summary
Premature birth is a major health problem worldwide. Preterm babies often develop apnoea of prematurity (AOP), which is commonly treated with caffeine. Trials indicate that preterm babies treated with low dose caffeine have less neurodevelopmental disabilities at 18 months. Higher doses of caffeine are often needed to reduce AOP but the risk of this is unknown. We will study the short and long-term effects of increasing doses of caffeine on the developing brain in a long-gestation species.
Analysis Of Viral And Cellular Gene Expression During Human Cytomegalovirus Latent Infection Of Hematopoietic Cells
Funder
National Health and Medical Research Council
Funding Amount
$407,545.00
Summary
Human cytomegalovirus (HCMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing HCMV disease. Like other herpesviruses, after initial infection HCMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body a ....Human cytomegalovirus (HCMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing HCMV disease. Like other herpesviruses, after initial infection HCMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body and no infectious virus is made. However, when conditions are right the virus can awaken (ie reactivate) from its latent state, producing new infectious virus and disease. It is in immunosuppressed individuals such as transplant patients that viral latency and reactivation are of most medical concern, yet viral latency remains very poorly understood. This project has three major components. Firstly, we aim to continue studies which are defining what viral genes are active (ie expressed) during latent infection. Identification of these genes and determination of how they function may have profound implications to our understanding of latency. Secondly, we will examine how human cells are affected when they become latently infected. A new and exciting technology called DNA microarray now makes it possible to examine the expression of many thousands of genes in a single experiment. For the first time, we will be able to determine how the cell changes during latency and reactivation. The study of viral and cellular gene expression during latency may contribute to the development of drugs which interfere with the viruses ability to become latent or reactivate. Thirdly, we have preliminary results which suggest that latent HCMV may actively avoid detection by the immune system. In this project we also aim to determine the mechanism by which the virus interferes with the expression of molecules which are an essential component of our immune system.Read moreRead less
Molecular Mechanisms Of Varicella Zoster Virus Interactions With Key Target Cells
Funder
National Health and Medical Research Council
Funding Amount
$421,650.00
Summary
Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes chickenpox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease . Herpes zoster affects many eder ....Varicella zoster virus (VZV) is a herpesvirus which infects up to 90% of the population. VZV causes chickenpox (varicella) predominantly in childhood and shingles (herpes zoster) in middle to old age people. Whilst VZV usually causes relatively mild disease in healthy individuals, VZV still causes significant morbidity in children and adults. VZV causes life-threatening disease in immunocompromised individuals such as patients who are elderly or have HIV disease . Herpes zoster affects many ederly individuals and a major complication is prolonged severe pain or post-herpetic neuralgia (PHN), both severely debilitating and which often requires follow-up medical care for months or years after the initial attack. Despite its significant impact on the community, little is known about the molecular details of how this virus functions. This project aims to improve our understanding of how VZV infection affects specialised human cells in order to make further advances in antiviral therapies as well improve vaccine design for the treatment or prevention of VZV disease and the crippling complication of PHN. This project has four components: (1) We will continue studies which have shown that VZV may actively avoid detection by the immune system. We aim to identify the mechanism and viral genes responsible for interfering with the expression of molecules which are essential for our immune system. (2) We will determine whether VZV infection of specialised immune cells (called dendritic cells) will affect their ability to function and interact with other immune cells (called T cells). (3) We will examine how VZV interacts in human nerve cells (neurons) and whether infected neurons undergo specially programmed cell death (apoptosis). (4) We will examine how different human cells change when they are infected with VZV. A new and exciting technology called DNA microarray now makes it possible to examine the expression of many thousands of genes in one experiment.Read moreRead less
Neuroactive Steroids In The Developing Brain: Potential For Preventing Perinatal Brain Damage
Funder
National Health and Medical Research Council
Funding Amount
$481,500.00
Summary
Complications during pregnancy, birth asphyxia or premature birth can lead to serious neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neuroactive steroids are a group of neuromodulators that are derived from the hormone progesterone. These steroids fall into two groups, those that appear to protect brain cells from damage caused by an inadequate supply of oxygen and those that may increase cell death. We have shown tha ....Complications during pregnancy, birth asphyxia or premature birth can lead to serious neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neuroactive steroids are a group of neuromodulators that are derived from the hormone progesterone. These steroids fall into two groups, those that appear to protect brain cells from damage caused by an inadequate supply of oxygen and those that may increase cell death. We have shown that protective neuroactive steroids are present in very large amounts in the fetal brain. Steroids produced by the placenta are converted to these neuroactive products by enzymes in the brain leading to the high levels that are seen during fetal life. Certain adverse conditions during pregnancy as well as preterm birth may cause marked changes in the balance of steroids that could increase susceptibility to brain injury. We have found that areas of the brain, where damage most often occurs, normally contain the highest amount of protective steroids, but only in late pregnancy. This suggests that disturbances that lower steroid production in these areas could contribute to the death of cells, particularly in mid-pregnancy and after premature birth. In the proposed studies, we will examine whether a toxic balance of steroids develops following adverse events in pregnancy as well as the areas of the brain where this is most pronounced. We will examine the changes in the expression of enzymes that can potentially cause the accumulation of protective steroids in the brain. We will then examine treatments that can raise the concentration of steroids and determine which combination of steroids best reduces cell death and brain injury following complications during pregnancy. The findings of this work will indicate the best therapeutic approach that may be adopted to modify the concentration of certain steroids so as to reduce the risk of brain damage in the fetus and neonate.Read moreRead less
Neurosteroid Mediated Protection After Birth: Approaches For Maximising Protective Steroid Levels In The Neonatal Brain
Funder
National Health and Medical Research Council
Funding Amount
$450,703.00
Summary
Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the ....Complications during pregnancy, birth asphyxia or premature birth can lead to neurological impairment in the newborn. Despite excellent neonatal care many of these babies go on to have serious handicaps. Neurosteroids are a group of steroids that regulate brain activity. These steroids protect brain cells from damage caused by an inadequate supply of oxygen by suppressing toxicity caused by excessive activity. We have shown that the levels of these protective steroids are remarkably high in the fetal brain and levels rise further in response to fetal stress. The placenta contributes steroid precursors that help maintain these high neurosteroid levels. This placenta-fetal brain interaction comprises an internal mechanism that protects the fetal brain from adverse events during pregnancy. At birth, however, there is a dramatic decline in neurosteroid concentrations in the brain after the loss of the placental precursor supply. The fall in concentrations is even greater in animals that are born growth restricted. This suggests that newborns, particularly those from compromised pregnancies, are at increased risk of brain damage due to low neurosteroid levels. We believe that certain commonly used steroid therapies may also lower steroid levels in the brain and result in increased vulnerability to brain damage during birth or in the early neonatal period. Alternatively, we propose that replacement of neurosteroid precursors in the newborn may raise brain neurosteroid levels and protect against brain damage. In the proposed studies we will evaluate treatments that can raise the concentration of steroids and determine the best strategy for reducing brain injury following complications during pregnancy, at birth and during the early newborn period. This work will determine the best therapeutic approaches for maximising neurosteroid-induced brain protection and for reducing the risk of brain damage.Read moreRead less
Viral And Host Cell Gene Expression During The Establishment And Maintenance Phases Of Human Cytomegalovirus Latency
Funder
National Health and Medical Research Council
Funding Amount
$149,250.00
Summary
Human cytomegalovirus (CMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing CMV disease. Like other herpesviruses, after initial infection CMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body and ....Human cytomegalovirus (CMV) is a herpesvirus which infects a majority of the population. HCMV is a significant cause of serious, life-threatening disease in neonates and in people who are immunosuppressed. Transplant recipients such as bone marrow, kidney and heart transplant patients are particularly at risk of developing CMV disease. Like other herpesviruses, after initial infection CMV can establish a life-long latent infection. During latency, the virus remains dormant in the human body and no infectious virus is made. However, when conditions are right the virus can awaken (ie reactivate) from its latent state, producing new infectious virus and disease. It is in immunosuppressed individuals such as transplant patients that viral latency and reactivation are of most medical concern, yet viral latency remains very poorly understood. The overall aim of these studies is to provide a much better understanding of how CMV latency is established and maintained, with the ultimate goal of making advances for the design of anti-viral therapies to disrupt these processes. This project has three major components: Firstly, we aim to identify and characterise viral gene expression during the establishment of latency and these findings will have profound implications to our understanding of latency. Secondly, we will examine how human cells are affected when they become latently infected. A new and exciting technology called DNA microarray now makes it possible to examine the expression of many thousands of genes in a single experiment. For the first time, we will be able to determine how the cell changes during the establishment and maintenance phases of latency. Thirdly, we will apply microarray technologies to determine how human cell genes are altered in response to the expression of individual viral genes that are active during the latent phase of infection.Read moreRead less
THE VASCULAR CONSEQUENCES OF SNORING AND OBSTRUCTIVE SLEEP APNOEA
Funder
National Health and Medical Research Council
Funding Amount
$476,052.00
Summary
Snoring refers to a condition where the throat narrows significantly during sleep, and allows the soft tissues which surround this part of the airway to vibrate and create the typical snoring noise. Habitual snoring is a very common problem in the adult population, with a prevalence of between 20-40%. More severe forms of snoring are associated with the obstructive sleep apnoea syndrome, which is a condition in which the throat completely blocks behind the tongue and palate during sleep leading ....Snoring refers to a condition where the throat narrows significantly during sleep, and allows the soft tissues which surround this part of the airway to vibrate and create the typical snoring noise. Habitual snoring is a very common problem in the adult population, with a prevalence of between 20-40%. More severe forms of snoring are associated with the obstructive sleep apnoea syndrome, which is a condition in which the throat completely blocks behind the tongue and palate during sleep leading to cessation of breathing for short periods of time. Sleep apnoea is among the commonest chronic disorders of adult males occurring in 5% of men over the age of 45 years. Increasingly, it is now recognised that snoring, without sleep apnoea, may be an independent risk factor for the development of both of these very common and significant medical disorders. However, there have been no studies exploring the mechanisms by which snoring might contribute to the development of stroke and hypertension. In this proposal, we will explore the hypothesis that chronic snoring transmits a pressure wave through the tissues of the neck to the carotid artery which is the main blood supply to the brain. We propose that the chronic vibration of this artery leads to disease such as atherosclerosis and hypertension. Our studies will help to prove that this is a common mechanism whereby both snoring and sleep apnoea may contribute to the development of important vascular diseases. Studies will also establish the prevalence of carotid atherosclerosis in snorers (with and without OSA), and the prevalence of habitual snoring and OSA in patients at risk of developoing completed stroke. The recognition of snoring as an independent risk factor for vascular disease will clearly have important and wide ranging implications for the future management of snoring in the prevention of stroke and hypertension.Read moreRead less