Pharmacological Targeting Via AKT, PTEN, And TGF-beta Pathway Integration Using Novel Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$634,875.00
Summary
We have identified potentially important interactions of cellular pathways that vary between individual sufferers, but which also provide common molecular targets for novel drug development. Our suite of novel and potent drugs that markedly and selectively inhibit cancer cell growth will be studied to determine if these pharmaceutical agents act to inhibit tumour cell proliferation by targeting common effector molecules of integrated cellular pathways.
Transport Of Amino Acids And Polyamines In The Malaria Parasite
Funder
National Health and Medical Research Council
Funding Amount
$415,631.00
Summary
Malaria is one of the major infectious diseases challenging the world today. There is no effective vaccine, and the malaria parasite has developed resistance to most of the antimalarial drugs that we presently have available. This work focuses on the molecular mechanisms by which the malaria parasite takes up particular classes of nutrients from the surrounding environment. It paves the way for the exploitation of these mechanisms as new and much-needed antimalarial drug targets.
Chloroquine Resistance And The Physiology Of The Malaria Parasite S Digestive Vacuole
Funder
National Health and Medical Research Council
Funding Amount
$287,921.00
Summary
Malaria is an infectious disease, caused by a single-celled parasite which invades the red blood cells of its human host. Each year, malaria causes the death of up to 3 million people, mostly children under the age of 5 The parasite has become resistant to most, if not all, of the antimalarial drugs presently available, and there is no vaccine. There is therefore an urgent need to develop new antimalarial drugs, and-or to devise strategies for overcoming the parasite s drug resistance mechanisms ....Malaria is an infectious disease, caused by a single-celled parasite which invades the red blood cells of its human host. Each year, malaria causes the death of up to 3 million people, mostly children under the age of 5 The parasite has become resistant to most, if not all, of the antimalarial drugs presently available, and there is no vaccine. There is therefore an urgent need to develop new antimalarial drugs, and-or to devise strategies for overcoming the parasite s drug resistance mechanisms. Chloroquine was, for many years, the mainstay of antimalarial chemotherapy and was, in many senses, a 'wonder-drug' cheap, safe and effective. However the emergence and spread of parasites that are resistant to chloroquine has meant that the drug is now largely useless as an antimalarial. Chloroquine kills (sensitive) parasite through an effect on the parasite s digestive vacuole an internal acidic compartment in which the parasite breaks down protein taken up from its host red blood cell. This compartment plays a crucial role in the growth and proliferation of the parasite. Yet we understand very little about its basic physiology, and nor do we understand the mechanism by which chloroquine-resistant parasites are able to survive exposure to the drug. The aim of the work proposed here is to gain an increased understanding of some of the mechanisms underlying the physiology of the parasite s digestive vacuole, as well as some of the factors influencing the accumulation of chloroquine within this compartment. The former part of the work may well reveal new antimalarial drug targets. The latter part of the work will increase our understanding of the mechanism of chloroquine resistance, thereby laying the groundwork for strategies by which these mechanisms might be circumvented and chloroquine-related drugs thereby restored to the front-line of our ongoing and increasingly desperate fight against malaria.Read moreRead less
The mechanisms controlling cell growth are often disrupted in cancers. We have identified on such growth control mechanism. When normal body cells are treated with a particular family of drugs known as histone deacetylase inhibitors, they react by stopping proliferating, but will resume normal growth when the drug is removed. However, we have found that similarly treated tumour cells are killed by these drugs. The difference between the normal and tumour cells is the functionality of a particula ....The mechanisms controlling cell growth are often disrupted in cancers. We have identified on such growth control mechanism. When normal body cells are treated with a particular family of drugs known as histone deacetylase inhibitors, they react by stopping proliferating, but will resume normal growth when the drug is removed. However, we have found that similarly treated tumour cells are killed by these drugs. The difference between the normal and tumour cells is the functionality of a particular growth control. The identification of how this growth control mechanism operates in normal cells, and defining the defect in tumour cells has the potential to identify new targets for more specific and potent anti-cancer drugs. The increased specificity, i.e. destruction of only the tumour cells while have little or no effect on the surround normal body tissue, would be extremely beneficial as one of the drawbacks to conventional anti-cancer treatments is their unwanted normal tissue toxicities. This is cause of the many debilitating side effects associated with chemo and radiotherapy which can limit the clinical effectiveness of these treatments.Read moreRead less
Novel Regulation Of RDNA Transcription By MTOR/S6K Signalling
Funder
National Health and Medical Research Council
Funding Amount
$393,750.00
Summary
Increased cellular growth requires a number of important processes to occur, the most fundamental of which is protein synthesis. Successful synthesis of proteins requires a large number of efficient ribosomes, the protein synthesis machinery. mTOR is a central cellular signalling molecule that directly regulates growth via modulating the efficiency of the ribosomes. It does this by regulating an enzyme called S6 kinase. Interestingly for long term or sustained increases in the rates of growth an ....Increased cellular growth requires a number of important processes to occur, the most fundamental of which is protein synthesis. Successful synthesis of proteins requires a large number of efficient ribosomes, the protein synthesis machinery. mTOR is a central cellular signalling molecule that directly regulates growth via modulating the efficiency of the ribosomes. It does this by regulating an enzyme called S6 kinase. Interestingly for long term or sustained increases in the rates of growth an increase in the number of ribosomes in addition to an increase efficiency of protein synthesis is required. This proposal will test the hypothesis that the mTOR-S6 kinase signalling pathway regulates protein synthesis both at the level of ribosome efficiency and capacity. This will be extended to determine the mechanism by which such regulation occurs. Furthermore recent studies have demonstrated that S6 kinase is involved in tumor growth. We propose that S6 kinase will contribute to the regulation of both normal or tumor growth at least in part via modulation of the number of ribosomes. Accordingly, S6K is upregulated in a segregated proportion of breast tumors. Outcomes from this project have the potential to provide targets to which specific therapies for particular breast tumors can be developed. Overall this information will also extend our basic knowledge on normal growth regulation.Read moreRead less
Metabolomic Analysis And Membrane Transport Proteins In The Malaria Parasite
Funder
National Health and Medical Research Council
Funding Amount
$368,875.00
Summary
The malaria parasite is a single celled organism which invades the red blood cells of those it infects. There is no vaccine and the parasite is becoming increasingly resistant to the drugs that we have available. There is therefore an urgent need for new antimalarial strategies. Research in this area has been helped by the sequencing of the genome of the parasite. However we still don t know what most of the genes in the parasite do, and it is not a straightforward matter to find out. One of the ....The malaria parasite is a single celled organism which invades the red blood cells of those it infects. There is no vaccine and the parasite is becoming increasingly resistant to the drugs that we have available. There is therefore an urgent need for new antimalarial strategies. Research in this area has been helped by the sequencing of the genome of the parasite. However we still don t know what most of the genes in the parasite do, and it is not a straightforward matter to find out. One of the things hampering us in our efforts to develop new antimalarial drugs is our relatively poor understanding of the sorts of biochemical pathways that the parasite relies on to support its high rate of growth and replication inside the red blood cell, as well the biochemical mechanisms that enable it to becomes drug-resistant. In this study we will use a range of modern analytical techniques to carry out the first detailed survey of the biochemical composition - the so-called metabolome - of the parasite. We will investigate how this changes in response to nutrient deprivation, in response to mutations in genes which play a key role in antimalarial drug resistance and in response to changes in the expression of genes encoding proteins which we believe to be involved in the uptake of nutrients by the parasite. This project will provide us with a wealth of new information about the biochemical make-up of the parasite, and it will provide new insights into the biochemical pathways that are operating and which might be targeted with new drugs. The work is likely to provide new insights into mechanisms of antimalarial drug resistance. It will also form the basis for a strategy that is likely to be extremely useful in helping us to ascribe function to the many genes involved in the biochemistry of this important human pathogen.Read moreRead less