I am a protein chemist working in signal transduction. The major focus of my research is to understand the molecular basis of the regulation of the PI3K-AKT-mTOR-S6K signalling pathway and how deregulation of the pathway is important in human cancer.
Activation Mechanisms Of The Hypoxia Inducible Factor-1a (HIF-1a) And The HIF-Like-Factor
Funder
National Health and Medical Research Council
Funding Amount
$316,650.00
Summary
A continual supply of oxygen is essential for normal functioning of the human body. When oxygen levels become limiting, the body attempts to rectify the situation by increasing the number of oxygen carrying red blood cells and promoting development of new blood vessels to increase the blood supply to tissues. Cells also adapt by altering their internal biochemistry and metabolism to decrease energy needs. These changes are the result of a genetic reprogramming within the cells. A major question ....A continual supply of oxygen is essential for normal functioning of the human body. When oxygen levels become limiting, the body attempts to rectify the situation by increasing the number of oxygen carrying red blood cells and promoting development of new blood vessels to increase the blood supply to tissues. Cells also adapt by altering their internal biochemistry and metabolism to decrease energy needs. These changes are the result of a genetic reprogramming within the cells. A major question is how the cells sense they are in a low oxygen environment and by what mechanisms they initiate genetic reprogramming. We are studying two proteins which have the ability to alter activity of genes when cells are stressed by hypoxia (low oxygen), and seek to discover how the proteins switch from latent forms to active forms in response to hypoxia. A greater understanding of the molecular mechanisms involved in the cellular hypoxic response is important to the development of new therapeutics for disease states involving disrupted oxygen flow (eg heart attack and stroke). Drugs which would block the hypoxic induced development of blood vessels could also be extremely beneficial in cancer treatment, as blocking blood supply to growing tumours can result in their starvation and shrinkage.Read moreRead less
Genome Maintenance And HSSB1, A Novel Player In The DNA Damage Response Pathway
Funder
National Health and Medical Research Council
Funding Amount
$646,822.00
Summary
We propose to characterize a novel player in the DNA damage response pathway. This study is expected to pave the way for the possible treatment of diseases that are caused by a nonfunctioning damage response pathway. There is an international effort to identify new proteins involved in this pathway and the funding of this proposal will provide leadership in Australia.
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
Roles Of Chaperone Proteins And Phosphorylation Events In Activity Of The Dioxin Receptor
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Polycyclic aromatic hydrocarbons (PAHs) are prevalent environmental pollutants which cause a wide range of deleterious health effects. Metabolic activation of PAHs occurs primarily through a set of intracellular oxidising enzymes which are induced by the presence of PAHs. The dioxin receptor is a gene regulatory protein that is pivotal in the metabolic pathway as it links the presence of contaminating PAHs to induction of the enzymes responsible for initiating their metabolism. While in many cas ....Polycyclic aromatic hydrocarbons (PAHs) are prevalent environmental pollutants which cause a wide range of deleterious health effects. Metabolic activation of PAHs occurs primarily through a set of intracellular oxidising enzymes which are induced by the presence of PAHs. The dioxin receptor is a gene regulatory protein that is pivotal in the metabolic pathway as it links the presence of contaminating PAHs to induction of the enzymes responsible for initiating their metabolism. While in many cases PAHs are oxidised to compounds which are water soluble and excretable (and therefore harmless), some substrates, such as benzo[a]pyrene found in cigarette smoke, can become inadvertently transformed into carcinogens. Other pollutants such as dioxin are resistant to metabolism and are extremely toxic. We have an ongoing interest in deciphering the biochemical pathways which lead to aberrant metabolism, and as such are studying the mechanistic role of the dioxin receptor in this process.Read moreRead less
Defining The Importance Of The AP-1 Transcription Factor In STAT1-independent Functions Of Interferon Gamma.
Funder
National Health and Medical Research Council
Funding Amount
$307,372.00
Summary
Interferons are soluble proteins released by immune cells that play a vital role in immune cell development, their recruitment to sites of injury-infection and detection and removal of pathogens. Interferons act by binding to the surfaces of other cells and altering their behaviour. This project will determine, at a molecular level, how this binding changes cell behaviour. These studies will help to explain why some people are prone to infectious disease.
Regulation And Function Of The Protein Tyrosine Phosphatase TCPTP In Mitosis
Funder
National Health and Medical Research Council
Funding Amount
$455,250.00
Summary
The cell cycle is a universal process by which cells reproduce and it underlies the growth and development of all living organisms. The most important events of the cell cycle concern the replication of chromosomal DNA during S phase and the separation of replicated DNA into progeny cells at mitosis. Mitosis is morphologically the most dynamic phase of the cell cycle and involves the precise coordination of many processes that are governed by reversible protein phosphorylation. Protein phosphata ....The cell cycle is a universal process by which cells reproduce and it underlies the growth and development of all living organisms. The most important events of the cell cycle concern the replication of chromosomal DNA during S phase and the separation of replicated DNA into progeny cells at mitosis. Mitosis is morphologically the most dynamic phase of the cell cycle and involves the precise coordination of many processes that are governed by reversible protein phosphorylation. Protein phosphatases play an important role in reversible protein phosphorylation and they are essential for mitosis. This grant proposal is focused on understanding the regulation and function of protein phosphatases in mitosis. Our studies will provide novel insight into processes mediating mitosis and may lead to the development of alternative strategies for treating cancer.Read moreRead less
Defining the pathways for the import of proteins into mitochondria. This application deals with the targeting of preproteins from the cytosol to the mitochondria in mammalian cells. The aims are to identify and characterise mitochondrial targeting signals within preproteins lacking typical N-terminal signal sequences; to characterise the roles of the cytosolic molecular chaperones such as Hsp90 and Hsp70 in assisting the movement of preproteins to the mitochondrial surface; to determine the inte ....Defining the pathways for the import of proteins into mitochondria. This application deals with the targeting of preproteins from the cytosol to the mitochondria in mammalian cells. The aims are to identify and characterise mitochondrial targeting signals within preproteins lacking typical N-terminal signal sequences; to characterise the roles of the cytosolic molecular chaperones such as Hsp90 and Hsp70 in assisting the movement of preproteins to the mitochondrial surface; to determine the interactions of both preproteins and cytosolic factors with outer membrane components and; to analyse the roles of individual TOM receptors in import. The results obtained will facilitate our understanding of general protein import processes and those specific for mammals.Read moreRead less