Molecular Toxinology Of Australian Box Jellyfish Venoms
Funder
National Health and Medical Research Council
Funding Amount
$283,110.00
Summary
Box jellyfish are an ongoing cause of illness and death for coastal communities and tourist regions in northern Australia. As well as creating a significant medical problem, the resulting closure of beaches during boxjellyfish 'season' results in an enormous loss of tourism income and threatens Australia's reputation as a safe destination. The jellyfish venoms contain toxins with potentially lethal effects on humans. For the first time, using pure venoms derived from the specialised stinging cel ....Box jellyfish are an ongoing cause of illness and death for coastal communities and tourist regions in northern Australia. As well as creating a significant medical problem, the resulting closure of beaches during boxjellyfish 'season' results in an enormous loss of tourism income and threatens Australia's reputation as a safe destination. The jellyfish venoms contain toxins with potentially lethal effects on humans. For the first time, using pure venoms derived from the specialised stinging cells (i.e. nematocytsts), we will isolate and characterize the major toxins from four species of box jellyfish. Their mechanism of action will be determined and the effect of various treatments such as antivenom will be investigated. This will also lead to the discovery of toxins with potentially novel targets and modes of action and increase our understanding of proposed treatments and prevention of stings.Read moreRead less
Cryptococcal Phospholipases: Structure, And Potential Targets For Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$511,650.00
Summary
Mortality and morbidity from invasive fungal infections have increased substantially over the past two decades, especially in immunocompromised patients, such as those with AIDS. Antifungal drugs marketed at present are not very effective or are toxic. There is a need to identify new metabolic and structural targets, some of which are responsible for fungal virulence, as potential areas for development of new drugs. One such virulence factor discovered in our laboratory is an enzyme secreted by ....Mortality and morbidity from invasive fungal infections have increased substantially over the past two decades, especially in immunocompromised patients, such as those with AIDS. Antifungal drugs marketed at present are not very effective or are toxic. There is a need to identify new metabolic and structural targets, some of which are responsible for fungal virulence, as potential areas for development of new drugs. One such virulence factor discovered in our laboratory is an enzyme secreted by the pathogenic fungus, Cryptococcus neoformans, which is acquired by inhalation into the lungs where it can cause lesions, and eventually spreads to other parts of the body, including the brain (median mortality, 17%). This enzyme breaks down cell membranes, aiding invasion into the host lungs and other tissues, and is called phospholipase B (PLB). It is also produced by several other pathogenic fungi, and is different from human phospholipases. In this project we aim to understand how the PLB is constructed, so that we can work out where the cell membrane components bind to it. We will then design drugs which can bind to the PLB enzyme in place of membrane components and in this way block its harmful effects. We will test the effects of such drugs to make sure they do not interfere with human enzyme systems. Inhibitory compounds may also be able to kill the cryptococcal cells, especially if administered together with currently used therapies. Drugs developed to treat Cryptococcus will then be applicable to other systemic fungal infections - a major advance in the treatment of fungal disease, and a saving of some A$60,000 per patient (estimated from a recent U.S. study).Read moreRead less
Role Of Sympathetic Nervous System In The Development Of Early Organ Damage In Obesity:an Emerging Target For Therapy
Funder
National Health and Medical Research Council
Funding Amount
$544,534.00
Summary
Young people with obesity often have no signs of cardiovascular disease but their organs, such as the heart, the kidneys and the blood vessels present early evidence of damage that can, in time, progress to confer cardiovascular risk. This study will look at the potential beneficial effect of a drug, by itself or in association with a low calorie diet, in reversing the progression of organ damage in young obese subjects.
Biochemical And Molecular Dissection Of The Mechanisms Controlling Ribosome Biogenesis By The PI3K/AKT/mTOR/MYC Network
Funder
National Health and Medical Research Council
Funding Amount
$545,180.00
Summary
Ribosome synthesis and function are critical for normal cell growth and division and hence this process is exquisitely regulated. Conversely, de-regulated cell growth can lead to cancer. We have identified new roles for the AKT and SGK families of kinases in controlling this process. This proposal aims to establish the mechanisms by which these enzymes control ribosome synthesis to better understand growth control and to provide insight for targeting these pathways in growth driven cancers.
Functional And Structural Studies Of A Glycosyltransferase Essential For Complex Glycolipid Biosynthesis In Mycobacteria
Funder
National Health and Medical Research Council
Funding Amount
$508,838.00
Summary
Tuberculosis (TB) kills more than three million people each year while the causative bacterial species, Mycobacterium tuberculosis, infects one-third of the entire human population. An alarmingly high rate of TB exists in Australia's indigenous population. This proposal aims to identify and characterise essential processes involved in synthesis of the outer coat of the bacterium which are potential targets for new drugs for the treatment of this devastating disease.
Regulation Of A Novel Target Gene, Aldehyde Dehydrogenase 1, By HOX11 In Childhood Leukaemia
Funder
National Health and Medical Research Council
Funding Amount
$382,027.00
Summary
Leukaemia is the most common cancer of childhood. Patients with the T-cell form of this disease (T-ALL), often carry specific chromosomal abnormalities that result in the activation of genes specifying transcription factors (TF's). TF's determine which genes are expressed in any given cell type, but when present in the wrong cell type at the wrong time may initiate cancer due to the combined activity of target genes under their control. The identification of target genes involved in cancer is th ....Leukaemia is the most common cancer of childhood. Patients with the T-cell form of this disease (T-ALL), often carry specific chromosomal abnormalities that result in the activation of genes specifying transcription factors (TF's). TF's determine which genes are expressed in any given cell type, but when present in the wrong cell type at the wrong time may initiate cancer due to the combined activity of target genes under their control. The identification of target genes involved in cancer is therefore essential in order to understand the mechanisms by which TF oncogenes induce tumour growth. However, very few target genes of TF's implicated in T-ALL have been discovered. HOX11 is one example of a TF aberrently expressed in childhood T-ALL. Recently we have shown that a gene called ALDH1 is under the control of HOX11 in a model cell system and also during normal development. The proper control of ALDH1 expression is important to the cell because it functions in the conversion of vitamin A to retinoic acid, a signalling molecule that critically affects cell growth and development. A related gene called RALDH2, that is also involved in retinoic acid synthesis, has very recently been shown to be under the control of other TF's implicated in T-ALL. These two discoveries therefore suggest that this disease may occur via a common pathway involving altered retinoic acid signalling. This project seeks to find out whether ALDH1 is also a target of HOX11 in T-ALL and if so, what effects it has on the cell. It also aims to determine how HOX11 influences the expression of ALDH1 and whether there are any other genes controlled by HOX11 that may be involved in tumour development. HOX11 provides an ideal model system to study the events leading to cancer that occur as a result of abnormal control of gene expression. Ultimately, such studies may lead to a better understanding of our normal biology as well as provide the basis for the design of improved cancer therapies.Read moreRead less