Novel Molecules Underlying The Development Of Corticopetal And Corticofugal Pathways
Funder
National Health and Medical Research Council
Funding Amount
$289,250.00
Summary
The mammalian brain consists of many discrete areas which perform specific functions. Each area has specific sets of connections with other brain areas. These sets of connections underlie the ability of the brain to execute functions critical to our daily lives, such as sight, hearing, touch and movement, as well as more complex functions such as memory, motivation and reasoning. We currently know little about how the sets of connections which underlie these functions are formed. The aim of this ....The mammalian brain consists of many discrete areas which perform specific functions. Each area has specific sets of connections with other brain areas. These sets of connections underlie the ability of the brain to execute functions critical to our daily lives, such as sight, hearing, touch and movement, as well as more complex functions such as memory, motivation and reasoning. We currently know little about how the sets of connections which underlie these functions are formed. The aim of this project is to understand how some of the connections between the cortex and other brain areas are formed during development. To do this the project will combine modern molecular techniques with neuroanatomy to identify molecules that are expressed by specific populations of neurons during critical developmental stages. These molecules will then be misexpressed in order to determine whether they are important for the development of appropriate connectivity in the brain. A knowledge of the molecules that regulate the development of neuronal pathways is critical to understanding brain development. In the long term, it will also lead to the development of therapies for cases when the brain is damaged or does not develop appropriately due to disease or injury.Read moreRead less
Molecular Characterisation And Diagnosis Of Malignant Mesothelioma
Funder
National Health and Medical Research Council
Funding Amount
$421,250.00
Summary
Malignant mesothelioma (MM) is an aggressive, asbestos-related tumour of increasing incidence throughout the world that is estimated to be cause approximately 20,000 deaths per annum . MM was rare until approximately 20-30 years ago but it is now more, or as, common a cause of death in Australia as cancers of the bone, liver, cervix, bladder and ovary. Although asbestos use has declined to virtually zero across most of the developed world, due to 30 to 40 year latency of the disease, the peak in ....Malignant mesothelioma (MM) is an aggressive, asbestos-related tumour of increasing incidence throughout the world that is estimated to be cause approximately 20,000 deaths per annum . MM was rare until approximately 20-30 years ago but it is now more, or as, common a cause of death in Australia as cancers of the bone, liver, cervix, bladder and ovary. Although asbestos use has declined to virtually zero across most of the developed world, due to 30 to 40 year latency of the disease, the peak in cases of mesothelioma is not expected until 2010. MM is one of the most aggressive and debilitating tumours known, with a median survival of 7-10 months and a clinical pattern that usually involves substantial pain and dyspnea. Advances in therapy-prevention of mesothelioma will have not only have a major health impact, but potentially an extraordinary economic impact. MM is predicted to cost the Australian economy around $5 billion in compensation over the next 35-40 years. Government, insurance companies and industry will share that cost. The significance of this disease therefore extends beyond its actual incidence. There is growing evidence in many tumour types that the best diagnostics and treatments for cancer will come about as a result of understanding the molecular logic that underpins carcinogenesis, and designing therapies and diagnostics accordingly. We will carry out a project using the most comprehensive microarrays available to profile gene expression in malignant mesothelioma. We will use the expression data we obtain to fulfil three aims. Firstly, we will use patient outcome information to search for genes whose expression is indicative of response to therapy. Secondly, we will search the data to identify candidate secreted molecules which may be useful in the early detection of MM. Finally, we will develop a molecular assay to unequivocally diagnose MM from cells collected from pleural effusions.Read moreRead less
High Resolution Genome-wide SNP Analysis Of Genetic Alterations In Early Ovarian Neoplasms
Funder
National Health and Medical Research Council
Funding Amount
$587,055.00
Summary
Ovarian cancer is the 5th leading cause of cancer death in women. For such a significant disease, remarkably little is know about its origins and this has limited progress in developing more effective diagnostic markers. We will undertake cutting edge genome-wide analysis of pre-invasive ovarian tumours to identify genetic markers relevant to malignancy. This work will significantly expand our understanding of how ovarian cancers develops.
Analysis And Regulation Of Leptospiral Virulence Factors.
Funder
National Health and Medical Research Council
Funding Amount
$630,465.00
Summary
Leptospirosis is a globally important infectious disease caused by Leptospira spp. This project aims to identify and characterise factors which play a role in disease development by knocking out genes, then investigating the impact on overall gene-protein expression in the mutant strain and its ability to cause disease. This will allow us to gain insights on mechanisms by which Leptospira spp. cause disease, leading to development of better methods of disease control and prevention.
The Transcriptional Profile Of A Metastatic Circulating Melanoma Cell
Funder
National Health and Medical Research Council
Funding Amount
$273,630.00
Summary
Melanoma is an aggressive skin cancer, and the leading cause of skin cancer related deaths. Disease spread is difficult to detect and difficult to cure. We previously identified circulating melanoma cells in patient peripheral blood and showed that their presence is associated with disease stage and recurrence. We will now fully characterise the phenotype of actively metastatic circulating melanoma cells for better patient prognosis and routine monitoring.
The Role Of Renin-angiotensin And Growth Factors In Developmental And Pathological Neovascularization In The Retina
Funder
National Health and Medical Research Council
Funding Amount
$342,562.00
Summary
In the normal retina of newborn babies, the blood vessels in the inner layers are not fully formed. These vessels are probably stimulated to grow by a reduction in retinal oxygen, which initiates the production of growth agents in retinal cells. Once the new vessels are formed the oxygen level of the retina becomes normal, and both the growth agents and blood vessel growth are reduced. A prolonged reduction in oxygen levels in the retina can have serious consequences for vision. Indeed, in some ....In the normal retina of newborn babies, the blood vessels in the inner layers are not fully formed. These vessels are probably stimulated to grow by a reduction in retinal oxygen, which initiates the production of growth agents in retinal cells. Once the new vessels are formed the oxygen level of the retina becomes normal, and both the growth agents and blood vessel growth are reduced. A prolonged reduction in oxygen levels in the retina can have serious consequences for vision. Indeed, in some eye diseases new blood vessel growth is excessive and the vessels are not properly formed, which leads to hemorrhage and ultimately blindness. Such events occur when the oxygen environment of premature babies is reduced after placement in high oxygen incubators. Also, in long-term diabetes, the oxygen levels of the retina falls as the retinal vessels become damaged. To understand the events that cause new vessel growth in retinal development and disease requires identification of the growth agents and their location in the retina. Very recently it has been found that the growth agent renin-angiotensin is made in the retina, and that its blockade in diabetic patients slows the progression of new retinal vessel growth. Renin-angiotensin is likely to cause its growth effects by increasing the production of other retinal growth agents. This proposal will study the role of renin-angiotensin and other growth agents in the developing newborn rat retina and in eye diseases. This information may lead to a further understanding of how blood vessels form in the retinas of newborn babies, and the production of new treatments for eye diseases characterized by blood vessel growth in the retina.Read moreRead less
Identification Of Porphyromonas Gingivalis Genes Required For Iron/haem Acquisition And Biofilm Formation
Funder
National Health and Medical Research Council
Funding Amount
$476,836.00
Summary
Periodontal diseases are some of the most common bacterial diseases of humans and along with dental caries, account for approximately 90% of all tooth loss in the Australian population. A recent survey of oral health in Australia found that in the 30-34 age group over 20% of people had moderate to severe periodontal disease, indicating that periodontitis is a major public health problem. Specific bacteria, especially Porphyromonas gingivalis, that grow as bacterial biofilms (dental plaque) cause ....Periodontal diseases are some of the most common bacterial diseases of humans and along with dental caries, account for approximately 90% of all tooth loss in the Australian population. A recent survey of oral health in Australia found that in the 30-34 age group over 20% of people had moderate to severe periodontal disease, indicating that periodontitis is a major public health problem. Specific bacteria, especially Porphyromonas gingivalis, that grow as bacterial biofilms (dental plaque) cause periodontal disease. In this study we will utilise the latest technology available to determine which genes of the bacterium are important for biofilm growth, iron acquisition and virulence in an animal model. We will investigate how the bacterium acquires iron, as there is usually little available iron for bacterial growth on human tissues and the ability of the bacterium to free itself from this iron limitation is associated with pathogenicity. The determination of the role of iron availability in biofilm formation and virulence of the bacterium will help us to understand the changes that occur in the initiation of disease and may allow the development of early intervention strategies. The significance of this work is that we will gain an understanding of how this bacterium functions as an opportunistic human pathogen. We will determine which genes are essential for growth as a biofilm and to produce disease in an animal model. This will enable the development of therapeutic and prophylactic interventions targeted to specific bacterial gene products required to produce disease.Read moreRead less
Primary central nervous system (CNS) tumours, arising in the brain and spinal cord, are the leading cause of cancer-related deaths in children less than 15 years of age. Medulloblastomas and other primitive neuroectodermal tumours (PNETs) are the most common form of primary childhood brain tumours, accounting for 25-30% of cases. Despite notable recent advances in our understanding of the molecular genetic basis of malignancies, the pathogenesis of CNS PNETs remains obscure. To address this prob ....Primary central nervous system (CNS) tumours, arising in the brain and spinal cord, are the leading cause of cancer-related deaths in children less than 15 years of age. Medulloblastomas and other primitive neuroectodermal tumours (PNETs) are the most common form of primary childhood brain tumours, accounting for 25-30% of cases. Despite notable recent advances in our understanding of the molecular genetic basis of malignancies, the pathogenesis of CNS PNETs remains obscure. To address this problem, we propose to apply a novel combinatorial approach for the identification of PNET tumour suppressor genes utilising both representational difference analysis (RDA) and microarray expression profiling. Data from this study will help to elucidate the molecular pathways that are compromised in the initiation and growth of PNETs. This information will have direct implications for the development of improved diagnostic and prognostic indicators necessary for the design of more effective therapeutic strategies for the treatment of PNET patients.Read moreRead less
A decade ago the adult brain was thought of as a structurally-fixed organ. Against this are well-documented cases of slow recovery after massive injuries or stroke. Simple models of brain injury using the tactile, visual and auditory systems of animals as models have now revealed multiple stages of recovery (plasticity). Some of these are inbuilt into the wiring of the neural systems such that functional plasticity can result without the need for any structural or cellular changes. A second grou ....A decade ago the adult brain was thought of as a structurally-fixed organ. Against this are well-documented cases of slow recovery after massive injuries or stroke. Simple models of brain injury using the tactile, visual and auditory systems of animals as models have now revealed multiple stages of recovery (plasticity). Some of these are inbuilt into the wiring of the neural systems such that functional plasticity can result without the need for any structural or cellular changes. A second group of plastic phenomena depend upon minute changes in the connections between neurons and these are invoked in the first few days following an injury (synaptic plasticity; changes in the pattern and strength of the connections between neurons). Aside from being model systems, there are also parallels of this plasticity with clinical situations such as losses in hearing and sight, and of the adaptations made by the brain in response to prosthetics (e.g. bionic ear) and resorative surgery but the degree of relevance for these situations is unclear. An intriguing aspect of the experiments on auditory and visual systems is that neurons with inputs from both ears, or both eyes, undergo the plastic changes when the relevant sense organ on only one side is damaged but the other is intact. In fact, on the basis of the limited available evidence, it appears that the changes are independent of there being a normal input from the other side. This is difficult to explain in terms of the modern understanding neuronal plasticity at a cellular level. It is thus proposed to study both auditory and visual models of this brain plasticity with stimuli which are systematically varied to extract the extent of bilateral interaction in the induced plasticity. This will enable prediction of how these plasticity mechanisms will be involved in adaptations made to prosthetics and surgical corrections.Read moreRead less
Polymicrobial Interactions In A Biofilm Of Periodontopathic Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$474,517.00
Summary
Chronic periodontitis is a bacterial-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. Three bacterial species in a biofilm (dental plaque) have been closely associated with chronic periodontitis in human ....Chronic periodontitis is a bacterial-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. Three bacterial species in a biofilm (dental plaque) have been closely associated with chronic periodontitis in humans and a fourth bacterial species has been suggested to assist colonisation of the biofilm by the three pathogenic species. The aim of this project is to use DNA microarray and proteomic techniques to study the interaction of the four bacterial species grown together in a polymicrobial biofilm. In particular genes of two of the pathogens, Porphyromonas gingivalis and Treponema denticola, important for biofilm formation and virulence in an animal model will be identified. This information will provide insight into the molecular processes of dental plaque formation and therfore molecular targets for the development of specific inhibitors that may have utility in the treatment and prevention of chronic periodontitis.Read moreRead less