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
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.
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