Structural Investigation Into The Regulation Of The Colony Stimulating Factor Receptor, C-FMS.
Funder
National Health and Medical Research Council
Funding Amount
$287,321.00
Summary
The colony stimulating factor receptor, c-FMS is a member of a family of protein signalling molecules expressed on the cell surface that are implicated in the development of serious diseases in humans, such as inflammatory diseases and cancer. A number of important proteins bind to and regulate c-FMS in different ways. I intend to visualise these interactions to further understand how c-FMS activity is controlled by alternative means.
Regulation Of The Cardiovascular Disease-Associated Protease Inhibitor Cystatin C For Therapeutic Application
Funder
National Health and Medical Research Council
Funding Amount
$498,505.00
Summary
Proteases can contribute to atherosclerosis, so they are normally controlled by the endogenous inhibitor, Cystatin C (Cst C). Some conditions cause reduction in Cst C levels and hence disease. On the other hand, excess Cst C can form toxic aggregates. In this project, we will identify mechanisms controlling Cst C expression and aggregation to find therapeutic strategies to treat cardiovascular diseases associated with Cst C.
Regulation Of Synthesis, Dimerisation And Secretion Of The Amyloidogenic Protease Inhibitor Cystatin C
Funder
National Health and Medical Research Council
Funding Amount
$423,565.00
Summary
The cells that compose our tissues are embedded in a complex mesh of extracellular proteins (for example collagen) that provide support, strenght and elasticity to the tissues. This extracellular matrix is not static; it is constantly remodelled when, for example, the cells of the immune system move through interstitial spaces to monitor the healthiness of the tissues. When infections or injuries occur, the inflammatory reactions that develop, and the processes involved in tissue repair, also in ....The cells that compose our tissues are embedded in a complex mesh of extracellular proteins (for example collagen) that provide support, strenght and elasticity to the tissues. This extracellular matrix is not static; it is constantly remodelled when, for example, the cells of the immune system move through interstitial spaces to monitor the healthiness of the tissues. When infections or injuries occur, the inflammatory reactions that develop, and the processes involved in tissue repair, also involve profound changes in the composition of the extracellular matrix. Such processes are also important for tumour growth; the cancer cells need to clear their way through interstitial space to escape to circulation and metastasize. During all these processes, the cells release to the extracellular space proteases that degrade collagen and the other components of the extracellular matrix. Obviously, these proteases must be tightly regulated to prevent them running out of control, so the cells also produce inhibitors of the proteases. The amount of proteases and inhibitors contained in the extracellular space must be maintained properly. If this equilibrium is disrupted, this can lead to pathology For instance, atherosclerosis is caused in part by excessive proteolysis of the blood vessel wall. In this project we want to study the mechanisms of one of the most abundant and important inhibitors of extracellular proteolysis: Cystatin C. We have discovered that certain cells of the immune system called dendritic cells posses interesting mechanisms to regulate how much Cystatin C they secrete. Furthermore, one of this mechanisms, which consists of pairing the protein to produce inactive dimers, may be the cause of some diseases characterised by accumulation of Cystatin C in the extracellular space. Our study may allow us to design therapies for the treatment of pathologies associated with defective or excessive production of Cystatin C.Read moreRead less
The Biosynthesis Of Mycobactin T, A Virulence Factor From Mycobacterium Tuberculosis.
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Mycobacterium tuberculosis is the causative agent of tuberculosis. The drug isoniazid led to a dramatic and sustained decline in mortality due to tuberculosis. This led to it being described in medical literature in 1988 as a disappearing disease which was now fairly easy to treat. However, the advent of HIV and the rapid rise of multidrug resistant M. tuberculosis led to dramatic changes. The risk that an HIV infected individual will develop active tuberculosis is 7% per year, compared to a lif ....Mycobacterium tuberculosis is the causative agent of tuberculosis. The drug isoniazid led to a dramatic and sustained decline in mortality due to tuberculosis. This led to it being described in medical literature in 1988 as a disappearing disease which was now fairly easy to treat. However, the advent of HIV and the rapid rise of multidrug resistant M. tuberculosis led to dramatic changes. The risk that an HIV infected individual will develop active tuberculosis is 7% per year, compared to a lifetime risk of 10% for an immunocompetent person. Similarly, the prevalence of drug resistant strains of M. tuberculosis is over 5% in many regions, including SE asia. Mycobacterial infections are regarded as the leading cause of morbidity and mortality world wide and WHO estimates that 30 million deaths will occur in the next decade due to these infections. Clearly, new drugs are required to combat the rising menace of this organism. The aim of this project is to detail the unique metabolic pathways in M. tuberculosis that produce Mycobactin T, essential to the virulence of this organism. Mycobactin T helps the bacteria obtain iron, an essential nutrient. These factors make the mycobaction pathway an ideal drug target and an understanding of its biochemistry is essential to its eventual exploitation for intervention in M. tuberculosis infections. We hypothesise that it may already provide the unknown site of action of a clinically employed, antituberculosis drug para-aminosalicylate (PAS). This project will i) fully define the structure of mycobactin T; ii) clone and overexpress key genes which catalyse the first three steps of mycobactin formation; iii) purify and characterise the overexpressed proteins with respect to their biochemical function; iv) examine the interaction of PAS with the proteins likely to be targeted by this antimycobacterial agent. The results of this work will provide the basis for the development of future anti-tuberculosis drugs.Read moreRead less
Identification of functionally important autophosphorylation site(s) on ataxia telangiectasia and Rad 3 - related (ATR) protein kinase. The integrity of our genetic material must be maintained so that it can be passed on from one generation to the next and also to minimize the risk of cancer and other pathologies in an individual. There are multiple proteins involved in protecting our DNA including several enzymes that detect and signal DNA damage to a series of pathways involved in halting the ....Identification of functionally important autophosphorylation site(s) on ataxia telangiectasia and Rad 3 - related (ATR) protein kinase. The integrity of our genetic material must be maintained so that it can be passed on from one generation to the next and also to minimize the risk of cancer and other pathologies in an individual. There are multiple proteins involved in protecting our DNA including several enzymes that detect and signal DNA damage to a series of pathways involved in halting the passage of cells through the cell cycle so that repair can occur. This project studies the mechanism of action of one of these enzymes which will be of benefit in designing new compounds to fight disease. Read moreRead less
Discovery And Mechanisms Of Host Cell Factors In HIV Uncoating
Funder
National Health and Medical Research Council
Funding Amount
$635,098.00
Summary
HIV entry into the host cell involves release of its capsid, a protein shell protecting the viral genome. The capsid hijacks host proteins to cloak itself from cellular defenses while the cell has evolved sensors that can block viral infection. This proposal aims to discover proteins involved in this arms race between host and virus and decipher how they control capsid disassembly. This insight will help design new drugs against HIV infection and new ways to deliver genes for gene therapies.
I am a protein crystallographer determining the structures of medically important proteins such as proteases. I am also a bioinformatician leading the development of informatics systems for automated highthroughput crystallography, and bioinformatic analy
Biochemical Reconstitution Of The Ubiquitin Ligase Pathway Defective In Fanconi Anaemia
Funder
National Health and Medical Research Council
Funding Amount
$562,742.00
Summary
Fanconi Anemia (FA) is characterised by loss of vital blood cells but also 700x risk of developing leukaemia and other cancers. FA is caused by an inherited defect in one of 15 different genes that provide a signal and repair mechanism protecting cells from cancer causing mutations. By reconstructing this signaling mechanism in the test tube we will determine how it contributes to cancer protection, and highlight potential strategies for treatment of FA and leukaemia in the general population.
Biochemical Analysis Of Akt 3-specific Signal Transduction
Funder
National Health and Medical Research Council
Funding Amount
$349,375.00
Summary
The Akt family of enzymes consists of 3 protein kinases (Akt 1,2 and 3) and has been shown to regulate many normal cellular processes such as cell proliferation, growth, survival and motility, as well as the growth of new blood vessels. All these processes are critical for cancers to grow. However, few studies have distinguished the roles of the individual family members. Our preliminary data revealed Akt3 is far more active than the other two forms. Furthermore, using our unique Akt3 specific a ....The Akt family of enzymes consists of 3 protein kinases (Akt 1,2 and 3) and has been shown to regulate many normal cellular processes such as cell proliferation, growth, survival and motility, as well as the growth of new blood vessels. All these processes are critical for cancers to grow. However, few studies have distinguished the roles of the individual family members. Our preliminary data revealed Akt3 is far more active than the other two forms. Furthermore, using our unique Akt3 specific antibody, we find Akt 3 protein and activity levels are high in rapidly proliferating ovarian cancer cell lines and in primary ovarian tumours. The aim of this proposal is to characterise the mode and role of signalling via Akt3, including the identification of targeted substrates and signaling pathways and the outcomes of Akt3 driven signaling on cellular properties. These studies will provide important clues to understanding how this family member functions in both health and disease. Elucidation of the basis of Akt3 dependent signalling will open the possibility for the development of drugs that interfere with Akt3 function (for example in high Akt 3 expressing tumours like those of the ovary). In the long term, extension of our profiling studies to other tumour types will give a novel insight into the extent of Akt3 de-regulation as a key mediator of cancer formation.Read moreRead less
Regulation Of SRC-Family And Focal Adhesion Kinase Function
Funder
National Health and Medical Research Council
Funding Amount
$381,338.00
Summary
Cells in our bodies stick to one another and to the cementing material called extracellular matrix surrounding them. An ezyme called focal adhesion kinase (FAK) is a major regulator of cell stickiness. It can catalyze the covalent attachment of a chemical group called phosphate to specific cellular protein. This proposal aims at studying how FAK is regulated by insulin stimulation and how FAK is regulated by a tumour suppressor called PTEN. Results of the study will shed light on how abberration ....Cells in our bodies stick to one another and to the cementing material called extracellular matrix surrounding them. An ezyme called focal adhesion kinase (FAK) is a major regulator of cell stickiness. It can catalyze the covalent attachment of a chemical group called phosphate to specific cellular protein. This proposal aims at studying how FAK is regulated by insulin stimulation and how FAK is regulated by a tumour suppressor called PTEN. Results of the study will shed light on how abberrations in the regulation and PTEN contribute to the development of development defects, heart attack, and the spreading of cancer cells.Read moreRead less