OVARIAN CANCER METASTASIS: Unraveling The Biology Of The Plasminogen Activation Cascade
Funder
National Health and Medical Research Council
Funding Amount
$169,875.00
Summary
Ovarian cancer affects 1,200 new Australians every year. Compared to breast cancer where research education and early screening have improved mortality rates, the incidence of ovarian cancer has not improved and death rates have more than doubled since 1930. With few overt symptoms, ovarian cancer has an extremely poor prognosis - a staggering 71% of women diagnosed with ovarian cancer will die from the disease, compared to 21% for breast cancer. Any studies which increase our understanding of t ....Ovarian cancer affects 1,200 new Australians every year. Compared to breast cancer where research education and early screening have improved mortality rates, the incidence of ovarian cancer has not improved and death rates have more than doubled since 1930. With few overt symptoms, ovarian cancer has an extremely poor prognosis - a staggering 71% of women diagnosed with ovarian cancer will die from the disease, compared to 21% for breast cancer. Any studies which increase our understanding of the biology of ovarian cancer metastasis may lead to new therapies designed to control these processes - as such this would be a major inroad into our fight against this cancer. The aim of this novel research project is to unravel the role that one cell surface system (the plasminogen (Plg) activation cascade) plays in determining the ability of ovarian cancer cells to metastasise and regulate new tumour blood vessel formation. This study addresses the paradoxical observations that this cascade can simultaneously facilitate cancer metastasis whilst concomitantly stopping new blood vessel formation in tumours. Using a number of advanced molecular cell biology methods, the hypothesis we will test is that the capacity of ovarian cancer to metastasise is determined by differential processing of plasminogen subsequent to cell-surface Plg binding. This results in a delicate balance between the generation of cell surface proteases and the release of protein fragments capable of stopping tumour blood vessel growth. Our group is well-equipped to address this hypothesis since we have already shown that: (1) Plg binding and activation is required for cancer cell invasion; (2) Plg binding and activation is elevated on malignant compared to benign cancers (3) Plg unfolds after it binds to cell surfaces or recombinant receptors; and, (4) Plg is easily fragmented to products that inhibit new blood vessel formation after binding to some cancer cells.Read moreRead less
2-Methoxyestradiol Analogues: Prototype Modulators Of Annexin II-dependent Plasminogen Activation
Funder
National Health and Medical Research Council
Funding Amount
$369,690.00
Summary
The enzyme system that enables us to dissolve blood clots is similar to the system that enables cancer cells to escape from the primary tumour and travel in the blood to another organ to form a secondary cancer growth. We have new results showing that some drug candidates can distinguish between these two closely related enzyme systems. We are now working to develop inhibitors that will stop cancer cells from spreading without compromising the ability to dissolve blood clots.
Molecular Characterization Of The Gingipains Of Porphyromonas Gingivalis
Funder
National Health and Medical Research Council
Funding Amount
$394,000.00
Summary
Chronic periodontitis is a bacteria-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. The bacterium Porphyromonas gingivalis has now been identified as a major pathogen in the development of chronic perio ....Chronic periodontitis is a bacteria-associated inflammatory disease of the supporting tissues of the teeth, which results in the destruction of tooth support and ultimately leads to tooth loss. The disease is a major public health problem with a large economic burden and has been associated with an increased risk of cardiovascular disease and pre-term birth and low birth weight. The bacterium Porphyromonas gingivalis has now been identified as a major pathogen in the development of chronic periodontitis. We have identified a major virulence factor of P. gingivalis which is an extracellular complex of proteins involved in binding and destroying host proteins. The aim of this proposal is to characterize the secretion, molecular processing and assembly of the cell surface complex using state-of-the-art proteomic techniques. This study will provide valuable insight into the molecular processes of a bacterial pathogen that leads to virulence. Detailed knowledge on the unique molecular events involved in secretion, processing and assembly of a major virulence factor will provide molecular targets for the development of specific inhibitors that may have utility as an adjunctive therapeutic and-or as part of a preventive regime or maintenance program for the control of chronic periodontitis. Further, the molecular insight that will result from this study will have broader application in the understanding of virulence factor processing of a Gram-negative pathogen that will provide paradigms for other bacterial pathogens.Read moreRead less
To Determine The Means By Which Plasminogen Activators Modulate Integrity Of The Blood Brain Barrier
Funder
National Health and Medical Research Council
Funding Amount
$523,084.00
Summary
Tissue-type plasminogen activator (t-PA) is used clinically to remove blood clots. However, t-PA can also cause brain injury and influence the blood brain barrier (BBB) which has implications for the treatment of patients with ischaemic stroke. This project will use in vitro and in vivo models to understand the mechanism by which t-PA modulates the BBB. A novel tPA variant will also be created that ultimately may be of benefit for patients with ischaemic stroke.